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Effects of photobiomodulation and a physical exercise program on the expression of inflammatory and cartilage degradation biomarkers and functional capacity in women with knee osteoarthritis: a randomized blinded study

Effects of photobiomodulation and a physical exercise program on the expression of inflammatory... Background: The knee osteoarthritis (OA) is a joint disease characterized by degradation of articular cartilage that leads to chronic inflammation. Exercise programs and photobiomodulation (PBM) are capable of modulating the inflammatory process of minimizing functional disability related to knee OA. However, their association on the concentration of biomarkers related to OA development has not been studied yet. The aim of the present study is to investigate the effects of PBM (via cluster) with a physical exercise program in functional capacity, serum inflammatory and cartilage degradation biomarkers in patients with knee OA. Methods: Forty-two patients were randomly allocated in 3 groups: ESP: exercise + sham PBM; EAP: exercise + PBM and CG: control group. Six patients were excluded before finished the experimental period. The analyzed outcomes in baseline and 8-week were: the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC) and the evalua- tion of serum biomarkers concentration (IL-1β, IL-6, IL-8, IL-10 e TNF-α, and CTX-II). Results: An increase in the functional capacity was observed in the WOMAC total score for both treated groups (p < 0.001) and ESP presents a lower value compared to CG (p < 0.05) the 8-week post-treatment. In addition, there was a significant increase in IL-10 concentration of EAP (p < 0.05) and higher value compared to CG (p < 0.001) the 8-week post-treatment. Moreover, an increase in IL-1β concentration was observed for CG (p < 0.05). No other differ - ence was observed comparing the other groups. Conclusion: Our data suggest that the physical exercise therapy could be a strategy for increasing functional capac- ity and in association with PBM for increasing IL-10 levels in OA knee individuals. Trial registration: ReBEC (RBR-7t6nzr). *Correspondence: patriciavassao@gmail.com Department of Biosciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Vassão et al. Adv Rheumatol (2021) 61:62 Page 2 of 10 Keywords: Knee osteoarthritis, Inflammation, Cytokines, Biomarkers, Photobiomodulation Introduction Another promising therapeutic intervention that has Osteoarthritis (OA) leads to degradation of articular been showing positive effects on degradation of cartilage cartilage, formation of osteophytes, decrease of joint tissue in the presence of OA is the low-level laser therapy space and degeneration of subchondral bone and is (LLLT) or more recently, photobiomodulation (PBM) characterized as a chronic joint disease [1]. These mor - [14, 15]. It is well known that PBM produces stimula- phological alterations culminate in an increasing of the tory effect on healing and has the ability of modulating level of articular pain, loss of function, decrease in the the inflammatory process in different tissues, including range of motion and muscle weakness, impairing the cartilage [5, 16]. Chondroprotective effects, inhibition quality of life of the patients [2]. of cartilage degradation, decreases in the expression of The pathogenesis of OA has relation with the increase chemotactic factors and inflammatory cytokines and of expression of specific cytokines and immune system increase antioxidant enzyme levels have been observed and, which contribute to cartilage degradation [3, 4]. It in several experimental model of OA in rats after PBM has been demonstrated that patients with OA showed [17, 18]. Also, clinical trials have demonstrated that PBM high levels of proinflammatory cytokines, which dis - is able of reducing pain, articular stiffness, knee swell - turb the catabolism and anabolism processes, being ing, increasing the functional performance in knee OA responsible by inflammation and consequence articu - patients [10, 19]. Alghadir, et  al. [20] showed that PBM lar cartilage degeneration [5]. In this context, the most (850  nm, 50mW, 6  J/point), applied in eight points on important cytokines involved in this process are Tumor knee during 4 weeks/ two times per week, improved the Necrosis Factor alpha (TNF-α), interleukin-1β (IL-1β) functional capacity evaluated by Western Ontario and and interleukin -6 (IL-6) [6]. As result of degradation of McMaster Universities Arthritis Index (WOMAC) in cartilage, a release of protein specific tissue fragments patients with knee OA (grade II or III). (neo-epitopes) in cleavage of type II collagen by matrix Furthermore, some authors have been investigat- metalloproteinases (MMPs) can be observe, especially ing the association of physical exercise and PBM on the with analyze of biomarker as C-telopeptide of type II management of OA symptoms [21, 22]. De Paula Gomes collagen (CTX-II) [7]. Based on this, the inhibition of et  al. [21] observed that PBM nine diode cluster device interleukins (ILs) activity and analysis of CTX-II as a (one 905 nm super-pulsed diode laser with, four 875 nm biomarker of progression of cartilage lesion are related light-emitting diode (LED) and four 640 nm LED) associ- to radiological grades of cartilage degradation and may ated to a physical exercise program had positive effects help to improved strategies to treat OA [8]. on reducing pain intensity in individuals with knee  OA. In this context, for OA, one of the most common Similar findings were observed by Alayat et  al., [23] and treatments is based on pharmacological intervention, de Matos Brunelli Braghin et al., [24]. mainly nonsteroidal and steroidal anti-inflammatory Although all the positive effects of physical exercise drugs (NSAIDs) [9]. However, the continuous use of programs for treatment of OA, its association with PBM NSAIDs can lead to severe adverse effects, like gas - via a cluster device on the expression of ILs and bio- trointestinal problems, and limited efficacy [10]. In an markers related to cartilage degradation in patients with attempt to attenuate these problems, alternative treat- OA has not been studied yet. In this context, based on ments have been studied including physical exercise the need of determining a more appropriate therapeutic programs, presenting positive effects on pain control, intervention to treat patients with OA, the present study joint dysfunction and disability in patients with OA aimed to investigate the effects of the incorporation of [11]. Furthermore, Castrogiovanni et  al. [12] dem- PBM (via cluster) into a physical exercise program in onstrated that the moderate physical activity (MPA) serum inflammatory biomarkers (IL-1β, IL-6, IL-8, IL-10 significantly increased on the expression of anti-inflam - e TNF-α), cartilage degradation biomarker (CTX-II) and matory [interleukin-4 (IL-4) and interleukin-10 (IL- functional capacity (WOMAC) in patients with knee OA. 10)] biomarkers in the synovium of an OA-induced rat model. The exercise protocol has been shown to Materials and methods have an anti-inflammatory effect, reducing levels of Study design and setting biomarkers like IL-6 and TNFα and suggesting that This is a single-blind (participants) randomized con - cytokine reduction can be an effective contribution for trolled trial. Ethical approval (Ethics in Human modulating pain due to OA [13]. Research Committee of the Federal University of São V assão et al. Adv Rheumatol (2021) 61:62 Page 3 of 10 Paulo- approval number 1.368.478) and written informed A researcher, who was not involved in the experiment, consent (patients signed) were obtained. The study was conducted the randomization process by a simple draw- conducted at the Laboratory of Manual and Physical ing through a computer program that created a random Resources and Balance Space – Fitness and Health from table of numbers and put these numbers (1, 2 and 3) on April 2018 to February 2020 and was logged with the opaque envelopes corresponding the group (ESP, EAP Brazilian Clinical Trials Registry (RBR-7t6nzr). All par- and CG), respectively. ticipants were recruited via advertisements in local news- Evaluation and reevaluation were performed by a papers and social media. researcher blinded to the experimental groups. Patients were also blinded to the mode of PBM application (sham or active). Patients As eligibility criteria, patients had aged between 55 and 70  years, present symptomatic OA in the previous Sample size 6  months, a diagnosis of unilateral or bilateral knee OA The sample size calculation was performed using the according to the American College of Rheumatology and GPower 3.0.10 program with parameters: effects size of a radiographic confirmation of OA (grades 2 or 3 of the 0.25 [27], power observed of 0.75 and α = 5%, considering Kellgren-Lawrence classification) [25]. The diagnosis of ANOVA model for three groups. The required sample knee OA was determined through an examination and would be 12 patients for each treatment group ESP, EAP the written opinion of a specialist in rheumatic diseases. or CG with a total of 36 patients. Each treatment group Also, patients should present BMI between 22 to 35  kg/ was started with 14 patients for possible dropout. m , criteria established by Pan American Health Organi- zation [26], more than 2 points on the Numeric Rating Experimental procedures Pain Scale and should be classified as active and irregu - After the initial evaluation, the following experimental larly active (physical activity with a frequency of at least 3 procedures were made 48  h before and 48  h after inter- times a week or a minimum of 150 min per week, accord- ventions: blood collection and functional capacity anal- ing to Criteria established by American College of Sports ysis (WOMAC). Participants of the control group were Medicine measures by the International Physical Activity oriented to maintain the same habits and do not start any Questionnaire – Short Version (IPAQ). new treatment for the period of 8 weeks. Patients were excluded if they have: fibromyalgia and/ or any kind of orthopedic or rheumatic diseases that may Assessments prevent the physical exercise; surgery of the knee within WOMAC questionnaire the past 6  months or joint replacement. Also, patients The functional capacity of lower limb and knee joint with diagnoses of lung diseases, cardiologic altera- could be evaluated by using Western Ontario and tions, uncontrolled hypertension, diabetes and had any McMaster Universities Osteoarthritis (WOMAC). The contraindications to PBM as cancer. During the study, WOMAC is a self-administered reliable and valid ques- patients who missed two consecutive training sessions or tionnaire for patients with hip and knee OA and used for more than 3 sessions along the treatment and who dis- assessment of pain, stiffness joints, and physical activity continued the pharmacological treatment for OA started of patients with hip and knee OA [28, 29]. The total score before the study were excluded. range of 0–96 and increased scores indicate a higher level of disability and lower level of quality of life. Randomization All patients met all inclusion criteria to participate in the study and signed a consent form. 42 patients were ran- Blood collection and serum biomarkers measurement domly allocated in ESP, EAP or CG groups, as observed One biomedical collected 8  ml of peripheral blood sam- below: ples from each patient before and after intervention period. After collected, the samples were centrifuged ESP: exercise + sham PBM, patients of this group to prepare the plasma and stored at -80  °C in cryogenic performed the physical exercise program associated tubes until in measurement. All the samples were sent to to PBM sham irradiation; a certificate laboratory for analyses. The enzyme-linked EAP: exercise + active PBM, patients of this group immunosorbent assays (ELISA) kits were used to ana- performed the physical exercise program associated lyze the levels of CTX-II (MyBioSource), IL-1β and IL-10 to active PBM irradiation. (Enzo Life Sciences, Inc.) and IL-6, IL-8 e TNF-α (Fine CG: control group, patients of this group were not Test ) following the procedures recommended by the submitted to any kind of therapeutical intervention. manufacturer with automated pipetting. Vassão et al. Adv Rheumatol (2021) 61:62 Page 4 of 10 Interventions Both groups, ESP and EAP, received the intervention excepted CG (waitlist). Physical exercise program The physical exercise protocol used was adapted from the study by Silva et  al. [30] and Foley et  al., [31]. A protocol with warming (5 min on treadmill), 6 strength exercises (Hip abductors and adductors chair, SLR – seated leg raise, Glute Bridge (Hip lift), Knee flexors and extensors chair) and stretching of major muscle groups was used for this purpose. The patients were subjected to a physical exercise protocol twice a week (Monday and Wednesday) for 8 consecutive weeks performed individually and supervised by a physical therapist. The application of the physical exercise protocol occurred according to 1-RM (repetition maximum) was deter- mined each 2 weeks for prescription and load progres- sion of the exercises. The exercise consisted 3 sets of 8 Fig. 1 PBMT irradiation points repetitions each, with 60% of 1-RM and a rest interval of 2–3 min between sets based on American Geriatrics Society [32] for patients with OA. The difference between groups was performed per-pro - tocol analysis. PBM via cluster A cluster with 7 diodes and an infrared wavelength Results (808 nm) was used in continuous mode, a 0.05cm spot Six patients (one from ESP, one from EAP and four from size, 100mW power output, 2  W/cm power density, CG) were excluded from the study due to the absence in 91  J/cm energy density, and energy of 4  J per point/ 2 consecutive treatment sessions. Table  1 displays the 56  J per knee, 40  s per application based on recom- baseline values of the outcome measures, anthropomet- mendations of the World Association of Laser Therapy ric and demographic characteristics of the participants [33]. The cluster dimension is 150  mm(L) × 100  mm( per group. Significant difference among ESP (p = 0.024), W) × 55  mm(H), with 1  cm of distance between infra- EAP (p = 0.009) and CG were identified for age. The EAP red diodes. After each training session for ESP and group showed higher values of BMI compared to CG EAP, respectively, sham or active PBM was applied on (p = 0.04). The percentage of the weight range for each medial and lateral region of knee affected for unilateral group was 15.4% normal weight, 69.2% overweight and OA and applied on medial and lateral region of most 15.4% obesity for ESP; 30.8% normal weigh, 38.4% over affected knee for bilateral OA (with knee positioned at weight and 30.8% obesity for EAP and 50% normal weigh, 45 degrees of flexion) (Fig.  1). A researcher responsi- 40% overweight and 10% obesity for CG. ble to conduct the intervention turned on the device of Figure  2 shows the baseline and 8-week values of PBM irradiation and immediately turned off the equip - WOMAC total score. The results demonstrated that ment to apply the sham PBM. there was significant difference between ESP, in the baseline compared to ESP in the 8-week (p = 0.00006), between EAP in the baseline and EAP in the 8-week Statistical analysis (p = 0.00002) and between ESP and CG in the 8-week To analyze the variables age, height, body mass, BMI, (p = 0.011). IL-1β, IL-6, IL-8, IL-10, TNF-α, CTX-II and WOMAC at The results of WOMAC pain, stiffness and function groups and evaluations, were performed the analysis of subscales are demonstrated in Table 2. There was signifi variance (ANOVA one-way and two-way test) followed by cant decrease in all domains for ESP and EAP compared Fisher’s post hoc test to identify the possible differences baseline with 8-week evaluation (p < 0,05) and significant among groups. The adopted significant value was α < 5%. decrease in WOMAC stiffness subscale for CG (p = 0.01). Data were expressed as mean ± standard deviation (SD). u Th s, in baseline values, significant difference was found V assão et al. Adv Rheumatol (2021) 61:62 Page 5 of 10 Table 1 Mean and SD of baseline values, anthropometric and demographic characteristics Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Mean SD Mean SD Mean SD Age (years) 62.29 ± 4.39 * 61.57 ± 4.42 * 66.5 ± 4.06 Height (m) 1.60 ± 0.04 1.60 ± 0.07 1.60 ± 0.06 Body mass (kg) 77.06 ± 10.34 78.6 ± 12.67 69.9 ± 7.29 BMI (kg/m ) 30.11 ± 3.64 30.49 ± 4.35 * 27.24 ± 2.99 Unilateral and Bilateral OA (%) 23% uni 77% bi 23% uni 77% bi 50% uni 50% bi WOMAC pain 7.43 ± 3.48 10.36 ± 2.76 9.1 ± 4.33 WOMAC stiffness 3.21 ± 2.51 2.57 ± 1.55 3.2 ± 2.34 &, WOMAC function 23 ± 11.36 30.5 ± 7.79 * 21.3 ± 9.25 WOMAC total 33.64 ± 15.92 43.43 ± 9.89 33.6 ± 9.86 IL-10 (pg/ml) 8.52 ± 2.09 8 ± 2.48 7.21 ± 1.39 IL-1β (pg/ml) 5.02 ± 0.52 5.47 ± 1.16 4.98 ± 0.64 CTX-II (ng/ml) 4.24 ± 0.78 4.10 ± 1.10 4.45 ± 0.48 IL-6 (pg/ml) 5.66 ± 0.35 5.61 ± 0.68 5.34 ± 0.13 IL-8 (pg/ml) 11.28 ± 2.54 11.25 ± 1.77 11.26 ± 1.81 TNF-α (pg/ml) 26.94 ± 14.88 26.38 ± 20.01 19.68 ± 1.19 ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group; BMI: body mass index; kg: kilograms; m: meter; uni: unilateral; bi: bilateral. IL-10: interleukin-10; IL-1β: interleukin-1β; CTX-II: C-telopeptide of type II collagen; IL-8: interleukin-8; TNF-α: Tumor Necrosis Factor alpha; WOMAC: Western Ontario and McMaster Universities Osteoarthritis statistical difference from CG statistical difference from ESP in WOMAC pain (p = 0.02) and function (p = 0.01) sub- scales 8-week. Figure  3 shows the baseline and 8-week values of the IL-10. It is possible to observe a statistical significant dif - ference between the values found for EAP in the baseline compared to the 8-week (p = 0.047). Also, a significant difference was found between the values of EAP and CG after the experimental period (p = 0.0009). For IL-1β expression, there was a significant increase and difference between the values found in the baseline and in the 8-week for CG (p = 0.016) (Fig. 4). Table  3 shows the values found in the baseline and in the 8-week of the pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and cartilage degradation biomarkers (CTX- II). For these variables, no significant difference was observed. Fig. 2 Values of WOMAC in the baseline and in the 8-week for all the experimental groups. WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group. statistical Discussion significance between in the baseline and in the 8-week. Statistical The results of this study demonstrated that the physical significance from ESP group in the same condition exercise program was able of increasing the functional capacity in the patients and, the associated treatments increased IL-10 expression compared to CG after the experimental period. In addition, IL-1β expression was between the EAP and ESP in WOMAC pain (p = 0.04) higher for CG comparing the values in the baseline and and function (p = 0,0001) subscales, and between EAP 8-week and no difference for the others biomarkers were and CG in WOMAC function subscale (p = 0.02). Sig- observed. nificant difference was found between the ESP and CG Vassão et al. Adv Rheumatol (2021) 61:62 Page 6 of 10 Table 2 Means and SD of Western Ontario and McMaster Universities Osteoarthritis Questionnaire Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Baseline 8-week Baseline 8-week Baseline 8-week Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD a a WOMAC pain 7.43 ± 3.48 3.36 ± 2.87 * 10.36 ± 2.76 4.79 ± 4.51 * 9.1 ± 4.33 7 ± 4.27 WOMAC stiffness 3.21 ± 2.51 1.21 ± 1.48 * 2.57 ± 1.55 1.43 ± 1.28 * 3.2 ± 2.35 1.7 ± 1.7 * a b a WOMAC function 23 ± 11.36 9.5 ± 7.38 * 30.5 ± 7.79 16.14 ± 10.7 * 21.3 ± 9.25 19.8 ± 11.45 WOMAC total score 33.64 ± 15.92 14.07 ± 10.99* 43.43 ± 9.89 22.36 ± 15.49* 33.60 ± 9.86 28.50 ± 15.95 ESP exercise and sham PBM group, EAP exercise and active PBM group, CG control group, WOMAC: Western Ontario and McMaster Universities Osteoarthritis statistical significance between in the baseline and in the 8-week statistical significance from ESP group in the same condition statistical significance from EAP group in the same condition Fig. 3 Values of IL-10 concentration in the baseline and in the 8-week for all the experimental groups. IL-10: interleukin-10; ESP: exercise and Fig. 4 Values of IL-1β concentration baseline and 8-week for all sham PBM group; EAP: exercise and active PBM group; CG: control the experimental groups. IL-1ß: interleukin-1ß; ESP: exercise and group. statistical significance between in the baseline and 8-week sham PBM group; EAP: exercise and active PBM group; CG: control values. statistical significance between in the 8-week values * group. Statistical significance between in the baseline and 8-week intervention values Knee OA is clinically associated with pain and loss of functional capacity, reaching 25% of the population with OA treated with physical exercises and PBM. One over the age of 60  years [34]. As described above, the hypothesis that can be raised is that the PBM param- lower WOMAC score demonstrated by the physical eters used in this study were not sufficient to produce exercised patients (irradiated or not with PBM) is pos- an additional effect in the exercised patients. sibly related to the increase in muscle strength after the Furthermore, it is well known that IL-10 has an exercise program, improving the joint stability and the important anti-inflammatory role in OA, presenting a level of pain, and consequently, leading to the improve- chondroprotective effect and, inhibiting chondrocyte ment of the functional capacity. Interestingly, PBM did apoptosis [38]. Our results showed that the active PBM not produce any extra positive effect in the exercised associated with physical exercises significantly increased patients. Data from the literature do not corroborate IL-10 expression after the experimental period of treat- the findings of the present study demonstrating a supe - ment. Assis et al., [17] also observed an increase of IL-10 rior effect measured by WOMAC in exercised and irra - expression in an experimental study, submitting rats with diated patients with OA [35–37]. Kheshie et al. [36] also OA to a program of aerobic exercises and PBM irradia- observed a decrease in WOMAC subscales in patients tion. All the positive effects may be related to the effects V assão et al. Adv Rheumatol (2021) 61:62 Page 7 of 10 Table 3 Means and SD of IL-10, IL-1b, IL-6, IL-8, TNF-α and CTX-II Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Baseline 8-week Baseline 8-week Baseline 8-week Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD IL-10 (pg/ml) 8.52 ± 2.09 8.44 ± 2.33 8.00 ± 2.48 9.98 ± 3.42*& 7.21 ± 1.39 6.54 ± 0.63 IL-1b (pg/ml) 5.02 ± 0.52 4.94 ± 0.49 5.47 ± 1.16 5.11 ± 0.92 4.98 ± 0.64 5.67 ± 1.99* CTX II (ng/ml) 4.24 ± 0.78 4.38 ± 0.63 4.10 ± 1.10 4.26 ± 0.65 4.45 ± 0.48 4.07 ± 0.98 IL-6 (pg/ml) 5.66 ± 0.35 5.57 ± 0.24 5.61 ± 0.68 5.65 ± 0.86 5.34 ± 0.13 5.37 ± 0.22 IL-8 (pg/ml) 11.28 ± 2.54 11.76 ± 2.97 11.25 ± 1.77 11.40 ± 1.73 11.26 ± 1.81 11.89 ± 1.85 TNF-α (pg/ml) 26.94 ± 14.88 26.24 ± 12.11 26.38 ± 20.01 23.00 ± 8.59 19.68 ± 1.19 19.42 ± 1.09 statistical significance between in the baseline and 8-week values statistical significance between in the 8-week values compare to CG group ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group of physical exercises and PBM on inflammatory mark - inflammatory cytokine IL-6 in OA animals [46]. How - ers. Physical exercises (and the related muscle contrac- ever, experimental studies indicate that PBM is capable of tion) produce a mechanotransduction stimulus, which modulating inflammatory mediators such as IL-6 in rats maintain homeostasis of articular cartilage and con- using an experimental model of joint inflammation [47]. tribute to attenuate OA physiological events [39]. As a The controversial results may be related to PBM param - consequence, physical exercise programs have anabolic, eters or the frequency if the treatment. anti-inflammatory and antioxidant effects in OA patients Furthermore, both treatments did not have any effect [40]. Moreover, many studies have demonstrated the on IL-8 and TNF-α cytokines concentration. IL-8 is anti-inflammatory effects of PBM [41, 42]. PBM is able to a chemokine produced by various inflammatory cells modulate mRNA gene expression of IL-10 in acute and such as neutrophils, basophils, macrophages and T cells chronic inflammatory phase and decreases the expres - [48]. TNF-α, a pro-inflammatory cytokine seems to be sion of this cytokine and consequently modulates the related to IL-1β (pro-inflammatory cytokine) because inflammatory process of OA [43]. Taking together, the are secreted by the same cells of the joint, in addition the combined treatments presented a positive effect on IL-10 increased presence of TNF-α stimulates the synthesis of expression, which could represent a modulation of the IL-6 and IL-8 [49]. These results corroborates with Hel - inflammatory process. mark et al., [50] who also observed that a resistance exer- IL-1β is considered one of the main cytokines in OA cise training (25 sets of 10 repetitions at 60% of 1-RM) development and the literature points out that the reduc- have not decreased the levels of IL-8 and IL-6 of patients tion of IL-1β production is an indication of the attenua- with knee OA. Aguiar et  al., [13] have not observed tion of cartilage degenerative process related to OA [44]. changes in TNF-α expression after 12  weeks of physi- CG demonstrated a significant increase of IL-1β expres - cal training using 60–80% of the maximum load of indi- sion after the experimental period. Similarly, an experi- viduals with knee OA. In addition, a study applied PBM mental study using rats with OA also observed a higher immediately after total knee arthroplasty and observed IL-1β expression in the control animals compared to the a decrease of IL-8 expression [49]. Moreover, a system- treated ones CG [45]. In this context, it can be suggested atic review and meta-analysis points out that the PBM that the treatments were able to positively kept stable the is capable of reduce considerably TNF-α expression in IL-1β expression. models of joint inflammation [47]. The results of the pre - IL-6, a pro-inflammatory cytokine has a catabolic sent study for IL-8 and TNF-α cytokines can be justified activity in the pathogenesis of OA. In the present study, by type and modality of the load used in physical exer- no significant difference in IL-6 expression was observed cises once it is suggested that maximum training load in both experimental periods for any group. Conversely, seems to modulate the levels of these cytokine [51]. Aguiar et  al., [13] found a significant reduction in IL-6 CTX-II is a biomarker released due to the degenera- levels in patients with knee OA, after a treatment of flex - tion of cartilage related to catabolic activity that leads to ibility training and muscle strengthening, 3 times a week loss of type II collagen concentration, which is the most for 12  weeks. Furthermore, a systematic review con- abundant protein of the cartilage matrix and proteogly- cluded that PBM has no effect on the expression of the can matrix of cartilage [52]. There was no statistically Vassão et al. Adv Rheumatol (2021) 61:62 Page 8 of 10 significant difference in CTX-II levels in this study. These • Physical exercise program and its association with findings do not corroborate those of with Nambi et  al. PBM had no effect on others pro-inflammatory and [1], which demonstrated that a protocol of PBM (905 nm, cartilage degradation biomarkers. super pulsed, 1.5 J per point, 12 J per knee) and exercise in patients with knee OA during 4 weeks (twice a week) were able of inhibiting CTX-II, MMP-3 (stromelysin), MMP-8 (collagenase-2), and MMP-13 (collagenase-3) Abbreviations expression. However, the study mentioned analyse the OA: Osteoarthritis; TNF-α: Tumor Necrosis Factor alpha; IL-1β: Interleukin-1β; levels of CTX-II fragments from urinary fraction and our IL-6: Interleukin -6; MMPs: Matrix metalloproteinases; CTX-II: C-telopeptide of type II collagen; NSAIDs: Nonsteroidal and steroidal anti-inflammatory study evaluated from the serum fraction of peripheral drugs; MPA: Moderate physical activity; ILs: Interleukins; LLLT: Low-level laser blood samples and this difference in analyse can justify therapy; PBM: Photobiomodulation; WOMAC: Western Ontario and McMaster the results of the present study. Universities Arthritis Index; LED: Light-emitting diode; ESP: Exercise sham pho- tobiomodulation group; EAP: Exercise active photobiomodulation group; CG: In addition, it may be suggested that PBM applica- Control group; ANOVA: Analysis of variance; ELISA: Enzyme-linked immuno- tion, through a cluster device constitutes an advantage sorbent assays; SLR: Seated leg raise; RM: Repetition maximum. for treating patients with knee OA, allowing the irradia- Acknowledgements tion of a larger area and optimizing the treatment [21]. Not applicable. Although some positive effects of the treatments in the patients in this study, some limitations can be raised as Authors’ contributions PGV, HTT and ACR–Conceptualization, methodology, data collection, writing- a minor number of patients in sample size. It would be original draft preparation and editing; RMDSC and LAG–methodology, statistic extremely important to assess the presence of inflamma - work, writing-reviewing and editing. CFDS—biomedicine responsible for tory markers in the synovial fluid, which would increase blood sample collection from volunteers. The author(s) read and approved the final manuscript. the accuracy of their analysis, as well as the possibility of correlating them with symptomatic variables. Also, there Funding is an absence of a follow-up in order to provide informa- This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo – 2016/08503–0. tion about the maintenance of results over time in these patients. Availability of data and materials Study data can be made available upon reasonable request to the principal investigator. Conclusion The results of this study demonstrated that the physical Declarations exercise program in association with PBM was capable of increasing IL-10 levels, and the physical exercise pro- Ethics approval and consent to participate All procedures were approved by the Ethics Committee of University gram improved the function capacity. However, PBM did (Approval Number 1368478) and, registered in www. clini caltr ials. gov, RBR- not promote an additional effect to the positive effects 7t6nzr. All participants gave their informed consent before participation. of exercise in improving pro-inflammatory and carti - Consent for publication lage degradation biomarkers, and functional capacity in Not applicable. women with knee OA. Thus, more studies need to be carried out, using other parameters, since the literature Competing interests The author(s) declare(s) that there is no conflict of interest. demonstrates heterogeneity in the parameters of treat- ment with PBM when associated with physical exercise, Author details for the consolidation of an intervention protocol for Department of Biosciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Depar tment patients with knee OA. of Human Movement Science, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Post Grad- Clinical messages uate Program of Interdisciplinary Health Sciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Scientific Institute and Technological Department -University Brazil, São • Patients who underwent physical exercise program in Paulo-Itaquera, SP, Brazil. association with PBM for 8  weeks showed improve- Received: 14 June 2021 Accepted: 5 October 2021 ment in IL-10 levels after treatment and when com- pared to the control group who did not any interven- tion; • The function capacity was improved in patients References undergoing a physical exercise program; 1. S GN, Kamal W, George J, Manssor E. Radiological and biochemical effects • Only the control group had the pro-inflammatory (CTX-II, MMP-3, 8, and 13) of low-level laser therapy (LLLT ) in chronic oste- oarthritis in Al-Kharj, Saudi Arabia. Lasers Med Sci. 2017; 32(2):297–303. marker (IL-1β) increased; V assão et al. Adv Rheumatol (2021) 61:62 Page 9 of 10 2. Duan ZX, Huang P, Tu C, Liu Q, Li SQ, Long ZL, Li ZH. MicroRNA-15a-5p 19. Soleimanpour H, Gahramani K, Taheri R, Golzari SE, Safari S, Esfanjani RM, regulates the development of osteoarthritis by targeting PTHrP in chon- Iranpour A. The effect of low-level laser therapy on knee osteoarthritis: drocytes. Biomed Res Int. 2019;2019(5):3904923. https:// doi. org/ 10. 1155/ prospective, descriptive study. Lasers Med Sci. 2014;29(5):1695–700. 2019/ 39049 23.https:// doi. org/ 10. 1007/ s10103- 014- 1576-6. 3. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The role of inflammatory 20. Alghadir A, Omar MT, Al-Askar AB, Al-Muteri NK. Eec ff t of low-level laser and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. therapy in patients with chronic knee osteoarthritis: a single-blinded Mediators Inflamm. 2014;2014: 561459. https:// doi. org/ 10. 1155/ 2014/ randomized clinical study. Lasers Med Sci. 2014;29(2):749–55. https:// doi. 561459.org/ 10. 1007/ s10103- 013- 1393-3. 4. Al-Khazraji BK, Appleton CT, Beier F, Birmingham TB, Shoemaker JK. 21. de Paula Gomes CAF, Leal-Junior ECP, Dibai-Filho AV, de Oliveira AR, Bley Osteoarthritis, cerebrovascular dysfunction and the common denomi- AS, Biasotto-Gonzalez DA, de Tarso Camillo de Carvalho P. Incorporation nator of inflammation: a narrative review. Osteoarthritis Cartilage. of photobiomodulation therapy into a therapeutic exercise program for 2018;26(4):462–70. https:// doi. org/ 10. 1016/j. joca. 2018. 01. 011. knee osteoarthritis: A placebo-controlled, randomized, clinical trial. Lasers 5. Tomazoni SS, Frigo L, Dos Reis Ferreira TC, Casalechi HL, Teixeira S, de Surg Med 2018; 50(8):819–828. doi: https:// doi. org/ 10. 1002/ lsm. 22939. Almeida P, Muscara MN, Marcos RL, Serra AJ, de Carvalho PTC, Leal-Junior 22. Alfredo PP, Bjordal JM, Junior WS, Lopes-Martins RÁB, Stausholm MB, ECP. Eec ff ts of photobiomodulation therapy and topical non-steroidal Casarotto RA, Marques AP, Joensen J. Long-term results of a randomized, anti-inflammatory drug on skeletal muscle injury induced by contusion controlled, double-blind study of low-level laser therapy before exercises in rats-part 1: morphological and functional aspects. Lasers Med Sci. in knee osteoarthritis: laser and exercises in knee osteoarthritis. Clin 2017;32(9):2111–20. https:// doi. org/ 10. 1007/ s10103- 017- 2346-z. Rehabil. 2018;32(2):173–8. https:// doi. org/ 10. 1177/ 02692 15517 723162. 6. Nefla M, Holzinger D, Berenbaum F, Jacques C. The danger from within: 23. Alayat MSM, Atya AM, Ali MME, Shousha TM. Correction to: Long-term alarmins in arthritis. Nat Rev Rheumatol. 2016;12(11):669–83. https:// doi. effect of high-intensity laser therapy in the treatment of patients with org/ 10. 1007/ s10103- 017- 2346-z. chronic low back pain: a randomized blinded placebo-controlled trial. 7. Severino RM, Jorge PB, Martinelli MO, deLima MV, Severino NR, Duarte Lasers Med Sci. 2020;35(1):297. https:// doi. org/ 10. 1007/ s10103- 019- Junior A. Analysis on the serum levels of the biomarker CTX-II in profes-02926-x. Errat umfor: Laser sMedS ci. 20142 9(3): 1065- 73. sional indoor soccer players over the course of one season. Rev Bras 24. de Matos Brunelli Braghin R, Libardi EC, Junqueira C, Rodrigues NC, Ortop. 2015;50(3):331–5. https:// doi. org/ 10. 1016/j. rboe. 2015. 04. 001. Nogueira-Barbosa MH, Renno ACM, Carvalho de Abreu DC. The effect of 8. Saberi Hosnijeh F, Siebuhr AS, Uitterlinden AG, Oei EH, Hofman A, Karsdal low-level laser therapy and physical exercise on pain, stiffness, function, MA, Bierma-Zeinstra SM, Bay-Jensen AC, van Meurs JB. Association and spatiotemporal gait variables in subjects with bilateral knee osteoar- between biomarkers of tissue inflammation and progression of osteo - thritis: a blind randomized clinical trial. Disabil Rehabil 2019; 41(26):3165– arthritis: evidence from the Rotterdam study cohort. Arthritis Res Ther. 3172. doi: https:// doi. org/ 10. 1080/ 09638 288. 2018. 14931 60. 2016;1(18):81. https:// doi. org/ 10. 1186/ s13075- 016- 0976-3. 25. Kellgren JH, Lawrence JS. Radiological assessment of rheumatoid arthritis. 9. Rannou F. [Prescribe non-pharmacological treatments for lower limb Ann Rheum Dis. 1957;16:485–93. osteoarthritis?]. Rev Prat 2012; 62(5):651–3. Review. French. 26. Organización Panamericana de la Salud. XXXVI Reunión del Comité Ase- 10. Wyszyńska J, Bal-Bocheńska M. Efficacy of high-intensity laser therapy sor de Investigaciones en Salud. Encuesta Multicéntrica: Salud Bienestar in treating knee osteoarthritis: a first systematic review. Photomed Laser y Envejecimiento (SABE) en América Latina y el Caribe [Internet]. 2011 Surg. 2018;36(7):343–53. https:// doi. org/ 10. 1089/ pho. 2017. 4425. Washington, D.C: Organización Panamericana de la Salud; Disponível em: 11. Bennell KL, Hall M, Hinman RS. Osteoarthritis year in review 2015: rehabili-http:// envej ecimi ento. csic. es/ docum entos/ docum entos/ paho- salud- 01. tation and outcomes. Osteoarthritis Cartilage. 2016;24(1):58–70. https:// pdf doi. org/ 10. 1016/j. joca. 2015. 07. 028. 27. » http:// envej ecimi ento. csic. es/ docum entos/ docum entos/ paho- salud- 12. Castrogiovanni P, Di Rosa M, Ravalli S, et al. Moderate physical activity as a 01. pdf prevention method for knee osteoarthritis and the role of synoviocytes as 28. Abd El-Kader SM, Al-Shreef FM, Al-Jiffri OH. Impact of aerobic exercise biological key. Int J Mol Sci. 2019;20(3):511. https:// doi. org/ 10. 3390/ ijms2 versus resisted exercise on endothelial activation markers and inflamma- 00305 11. tory cytokines among elderly. Afr Health Sci. 2019;19(4):2874–80. https:// 13. Aguiar GC, Do Nascimento MR, De Miranda AS, Rocha NP, Teixeira AL, doi. org/ 10. 4314/ ahs. v19i4.9. Scalzo PL. Eec ff ts of an exercise therapy protocol on inflammatory mark - 29. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Valida- ers, perception of pain, and physical performance in individuals with tion study of WOMAC: a health status instrument for measuring knee osteoarthritis. Rheumatol Int. 2015;35(3):525–31. https:// doi. org/ 10. clinically important patient relevant outcomes to antirheumatic drug 1007/ s00296- 014- 3148-2. therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 14. Assis L, Milares LP, Almeida T, Tim C, Magri A, Fernandes KR, Medalha C, 1988;15(12):1833–40. Muniz Renno AC. Aerobic exercise training and low-level laser therapy 30. Choquette D, Bellamy N, Raynauld JP. A French-Canadian version of the modulate inflammatory response and degenerative process in an WOMAC osteoarthritis index. Arthritis Rheum. 1994;37:S226. experimental model of knee osteoarthritisin rats. Osteoarthr Cartil. 31. Silva LE, Valim V, Pessanha AP, Oliveira LM, Myamoto S, Jones A, Natour J. 2016;24:169–77. https:// doi. org/ 10. 1007/ s00296- 014- 3148-2. Hydrotherapy versus conventional land-based exercise for the manage- 15. Balbinot G, Schuch CP, Nascimento PSD, Lanferdini FJ, Casanova M, ment of patients with osteoarthritis of the knee: a randomized clinical Baroni BM, Vaz MA. Photobiomodulation therapy partially restores trial. Phys Ther. 2008;88:12–21. https:// doi. org/ 10. 2522/ ptj. 20060 040. cartilage integrity and reduces chronic pain behavior in a rat model 32. Foley A, Halbert J, Hewitt T, Crotty M. Does hydrotherapy improve of osteoarthritis: involvement of spinal glial modulation. Cartilage. strength and physical function in patients with osteoarthritis–a ran- 2019;30:1947603519876338. https:// doi. org/ 10. 1177/ 19476 03519 876338. domised controlled trial comparing a gym based and a hydrotherapy 16. Hamblin MR. Mechanisms and applications of the anti-inflammatory based strengthening programme. Ann Rheum Dis. 2003;62:1162–7. effects of photobiomodulation. AIMS Biophys. 2017;4(3):337–61. https:// https:// doi. org/ 10. 1136/ ard. 2002. 005272. doi. org/ 10. 3934/ biophy. 2017.3. 337. 33. American Geriatrics Society Panel on Exercise and Osteoarthritis. Exercise 17. Assis L, Tim C, Magri A, Fernandes KR, Vassão PG, Renno ACM. Inter- prescription for older adults with osteoarthritis pain: consensus practice leukin-10 and collagen type II immunoexpression are modulated by recommendations. A supplement to the AGS Clinical Practice Guide- photobiomodulation associated to aerobic and aquatic exercises in an lines on the management of chronic pain in older adults. J Am Geriatr experimental model of osteoarthritis. Lasers Med Sci. 2018;33(9):1875–82. Soc 2001; 49(6):808–823 Review. Erratum in: J Am Geriatr Soc 2001 https:// doi. org/ 10. 1007/ s10103- 018- 2541-6. Oct;49(10):1400 18. de Oliveira VL, Silva JA Jr, Serra AJ, Pallotta RC, da Silva EA, de Farias 34. World Association of Laser Therapy ( WALT ). Consensus agreement on the Marques AC, Feliciano RD, Marcos RL, Leal-Junior EC, de Carvalho PT. design and conduct of clinical studies with low- level laser therapy and Photobiomodulation therapy in the modulation of inflammatory light therapy for musculoskeletal pain and disorders. Photomed Laser mediators and bradykinin receptors in an experimental model of acute Surg. 2006;24:761–2. osteoarthritis. Lasers Med Sci. 2017;32(1):87–94. https:// doi. org/ 10. 1007/ 35. Alcalde GE, Fonseca AC, Bôscoa TF, et al . Eec ff t of aquatic physical s10103- 016- 2089-2. therapy on pain perception, functional capacity and quality of life in Vassão et al. Adv Rheumatol (2021) 61:62 Page 10 of 10 older people with knee osteoarthritis: study protocol for a randomized 45. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of controlled trial. Trials 2017; 18(1):317. Published 2017 Jul 11. doi:https:// proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat doi. org/ 10. 1186/ s13063- 017- 2061-x. Rev Rheumatol. 2011;7(1):33–42. https:// doi. org/ 10. 1038/ nrrhe um. 2010. 36. Alfredo PP, Bjordal JM, Dreyer SH, Meneses SR, Zaguetti G, Ovanessian 196. V, Fukuda TY, Junior WS, Lopes Martins RÁ, Casarotto RA, Marques AP. 46. Sanches M, Assis L, Criniti C, Fernandes D, Tim C, Renno ACM. Chondroi- Efficacy of low level laser therapy associated with exercises in knee osteo - tin sulfate and glucosamine sulfate associated to photobiomodulation arthritis: a randomized double-blind study. Clin Rehabil. 2012;26:523–33. prevents degenerative morphological changes in an experimental model https:// doi. org/ 10. 1016/ S2255- 4971(15) 30407-9. of osteoarthritis in rats. Lasers Med Sci. 2018;33(3):549–57. https:// doi. 37. Kheshie AR, Alayat MS, Ali MM. High-intensity versus low-level laser ther-org/ 10. 1007/ s10103- 017- 2401-9. apy in the treatment of patients with knee osteoarthritis: a randomized 47. Nambi G. Does low level laser therapy has effects on inflammatory bio - controlled trial. Lasers Med Sci. 2014;29(4):1371–6. https:// doi. org/ 10. markers IL-1β, IL-6, TNF-α, and MMP-13 in osteoarthritis of rat models-a 1007/ s10103- 014- 1529-0. systemic review and meta-analysis. Lasers Med Sci. 2021;36(3):475–84. 38. Nazari A, Moezy A, Nejati P, Mazaherinezhad A. Efficacy of high-intensity https:// doi. org/ 10. 1007/ s10103- 020- 03124-w. laser therapy in comparison with conventional physiotherapy and exer- 48. Alves AC, Vieira R, Leal-Junior E, dos Santos S, Ligeiro AP, Albertini R, Junior cise therapy on pain and function of patients with knee osteoarthritis: J, de Carvalho P. Eec ff t of low-level laser therapy on the expression of a randomized controlled trial with 12-week follow up. Lasers Med Sci. inflammatory mediators and on neutrophils and macrophages in acute 2019;34(3):505–16. https:// doi. org/ 10. 1007/ s10103- 018- 2624-4. joint inflammation. Arthritis Res Ther. 2013;15(5):R116. https:// doi. org/ 10. 39. Kwon JY, Lee SH, Na HS, Jung K, Choi J, Cho KH, Lee CY, Kim SJ, Park 1186/ ar4296. SH, Shin DY, Cho ML. Kartogenin inhibits pain behavior, chondrocyte 49. Hoff P, Buttgereit F, Burmester GR, Jakstadt M, Gaber T, Andreas K, inflammation, and attenuates osteoarthritis progression in mice through Matziolis G, Perka C, Röhner E. Osteoarthritis synovial fluid activates induction of IL-10. Sci Rep. 2018; 14;8(1):13832. doi: https:// doi. org/ 10. pro-inflammatory cytokines in primary human chondrocytes. Int Orthop. 1038/ s41598- 018- 32206-7. 2013;37(1):145–51. https:// doi. org/ 10. 1007/ s00264- 012- 1724-1. 40. Bader DL, Salter DM, Chowdhury TT. Biomechanical influence of car - 50. Langella LG, Casalechi HL, Tomazoni SS, Johnson DS, Albertini R, Pallotta tilage homeostasis in health and disease. Arthritis. 2011;2011:979032. RC, Marcos RL, de Carvalho PTC, Leal-Junior ECP. Photobiomodula- doi: https:// doi. org/ 10. 1155/ 2011/ 979032. Epub 2011 Sep 15. PMID: tion therapy (PBMT ) on acute pain and inflammation in patients who 22046527; PMCID: PMC3196252. underwent total hip arthroplasty-a randomized, triple-blind, placebo- 41. Cifuentes DJ, Rocha LG, Silva LA, Brito AC, Rueff-Barroso CR, Porto LC, controlled clinical trial. Lasers Med Sci. 2018;33(9):1933–40. https:// doi. Pinho RA. Decrease in oxidative stress and histological changes induced org/ 10. 1007/ s10103- 018- 2558-x. by physical exercise calibrated in rats with osteoarthritis induced by 51. Helmark IC, Mikkelsen UR, Børglum J, Rothe A, Petersen MC, Andersen monosodium iodoacetate. Osteoarthritis Cartilage. 2010;18(8):1088–95. O, Langberg H, Kjaer M. Exercise increases interleukin-10 levels both https:// doi. org/ 10. 1016/j. joca. 2010. 04. 004. intraarticularly and peri-synovially in patients with knee osteoarthritis: a 42. Pigatto GR, Silva CS, Parizotto NA. Photobiomodulation therapy reduces randomized controlled trial. Arthritis Res Ther. 2010;12(4):R126. https:// acute pain and inflammation in mice. J Photochem Photobiol B. doi. org/ 10. 1186/ ar3064. 2019;196: 111513. https:// doi. org/ 10. 1016/j. jphot obiol. 2019. 111513. 52. Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF. Resistance 43. Li K, Liang Z, Zhang J, Zuo X, Sun J, Zheng Q, Song J, Ding T, Hu X, Wang exercise decreases skeletal muscle tumor necrosis factor alpha in frail Z. Attenuation of the inflammatory response and polarization of mac- elderly humans. FASEB J. 2001;15(2):475–82. https:// doi. org/ 10. 1096/. fj 00- rophages by photobiomodulation. Lasers Med Sci. 2020;35(7):1509–18. 0274c om. https:// doi. org/ 10. 1007/ s10103- 019- 02941-y. 44. Casalechi HL, Leal-Junior EC, Xavier M, Silva JA Jr, de Carvalho PD, Publisher’s Note Aimbire F, Albertini R. Low-level laser therapy in experimental model Springer Nature remains neutral with regard to jurisdictional claims in pub- of collagenase-induced tendinitis in rats: effects in acute and chronic lished maps and institutional affiliations. inflammatory phases. Lasers Med Sci. 2013;28(3):989–95. https:// doi. org/ 10. 1007/ s10103- 012- 1189-x. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Effects of photobiomodulation and a physical exercise program on the expression of inflammatory and cartilage degradation biomarkers and functional capacity in women with knee osteoarthritis: a randomized blinded study

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10.1186/s42358-021-00220-5
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Abstract

Background: The knee osteoarthritis (OA) is a joint disease characterized by degradation of articular cartilage that leads to chronic inflammation. Exercise programs and photobiomodulation (PBM) are capable of modulating the inflammatory process of minimizing functional disability related to knee OA. However, their association on the concentration of biomarkers related to OA development has not been studied yet. The aim of the present study is to investigate the effects of PBM (via cluster) with a physical exercise program in functional capacity, serum inflammatory and cartilage degradation biomarkers in patients with knee OA. Methods: Forty-two patients were randomly allocated in 3 groups: ESP: exercise + sham PBM; EAP: exercise + PBM and CG: control group. Six patients were excluded before finished the experimental period. The analyzed outcomes in baseline and 8-week were: the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC) and the evalua- tion of serum biomarkers concentration (IL-1β, IL-6, IL-8, IL-10 e TNF-α, and CTX-II). Results: An increase in the functional capacity was observed in the WOMAC total score for both treated groups (p < 0.001) and ESP presents a lower value compared to CG (p < 0.05) the 8-week post-treatment. In addition, there was a significant increase in IL-10 concentration of EAP (p < 0.05) and higher value compared to CG (p < 0.001) the 8-week post-treatment. Moreover, an increase in IL-1β concentration was observed for CG (p < 0.05). No other differ - ence was observed comparing the other groups. Conclusion: Our data suggest that the physical exercise therapy could be a strategy for increasing functional capac- ity and in association with PBM for increasing IL-10 levels in OA knee individuals. Trial registration: ReBEC (RBR-7t6nzr). *Correspondence: patriciavassao@gmail.com Department of Biosciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Vassão et al. Adv Rheumatol (2021) 61:62 Page 2 of 10 Keywords: Knee osteoarthritis, Inflammation, Cytokines, Biomarkers, Photobiomodulation Introduction Another promising therapeutic intervention that has Osteoarthritis (OA) leads to degradation of articular been showing positive effects on degradation of cartilage cartilage, formation of osteophytes, decrease of joint tissue in the presence of OA is the low-level laser therapy space and degeneration of subchondral bone and is (LLLT) or more recently, photobiomodulation (PBM) characterized as a chronic joint disease [1]. These mor - [14, 15]. It is well known that PBM produces stimula- phological alterations culminate in an increasing of the tory effect on healing and has the ability of modulating level of articular pain, loss of function, decrease in the the inflammatory process in different tissues, including range of motion and muscle weakness, impairing the cartilage [5, 16]. Chondroprotective effects, inhibition quality of life of the patients [2]. of cartilage degradation, decreases in the expression of The pathogenesis of OA has relation with the increase chemotactic factors and inflammatory cytokines and of expression of specific cytokines and immune system increase antioxidant enzyme levels have been observed and, which contribute to cartilage degradation [3, 4]. It in several experimental model of OA in rats after PBM has been demonstrated that patients with OA showed [17, 18]. Also, clinical trials have demonstrated that PBM high levels of proinflammatory cytokines, which dis - is able of reducing pain, articular stiffness, knee swell - turb the catabolism and anabolism processes, being ing, increasing the functional performance in knee OA responsible by inflammation and consequence articu - patients [10, 19]. Alghadir, et  al. [20] showed that PBM lar cartilage degeneration [5]. In this context, the most (850  nm, 50mW, 6  J/point), applied in eight points on important cytokines involved in this process are Tumor knee during 4 weeks/ two times per week, improved the Necrosis Factor alpha (TNF-α), interleukin-1β (IL-1β) functional capacity evaluated by Western Ontario and and interleukin -6 (IL-6) [6]. As result of degradation of McMaster Universities Arthritis Index (WOMAC) in cartilage, a release of protein specific tissue fragments patients with knee OA (grade II or III). (neo-epitopes) in cleavage of type II collagen by matrix Furthermore, some authors have been investigat- metalloproteinases (MMPs) can be observe, especially ing the association of physical exercise and PBM on the with analyze of biomarker as C-telopeptide of type II management of OA symptoms [21, 22]. De Paula Gomes collagen (CTX-II) [7]. Based on this, the inhibition of et  al. [21] observed that PBM nine diode cluster device interleukins (ILs) activity and analysis of CTX-II as a (one 905 nm super-pulsed diode laser with, four 875 nm biomarker of progression of cartilage lesion are related light-emitting diode (LED) and four 640 nm LED) associ- to radiological grades of cartilage degradation and may ated to a physical exercise program had positive effects help to improved strategies to treat OA [8]. on reducing pain intensity in individuals with knee  OA. In this context, for OA, one of the most common Similar findings were observed by Alayat et  al., [23] and treatments is based on pharmacological intervention, de Matos Brunelli Braghin et al., [24]. mainly nonsteroidal and steroidal anti-inflammatory Although all the positive effects of physical exercise drugs (NSAIDs) [9]. However, the continuous use of programs for treatment of OA, its association with PBM NSAIDs can lead to severe adverse effects, like gas - via a cluster device on the expression of ILs and bio- trointestinal problems, and limited efficacy [10]. In an markers related to cartilage degradation in patients with attempt to attenuate these problems, alternative treat- OA has not been studied yet. In this context, based on ments have been studied including physical exercise the need of determining a more appropriate therapeutic programs, presenting positive effects on pain control, intervention to treat patients with OA, the present study joint dysfunction and disability in patients with OA aimed to investigate the effects of the incorporation of [11]. Furthermore, Castrogiovanni et  al. [12] dem- PBM (via cluster) into a physical exercise program in onstrated that the moderate physical activity (MPA) serum inflammatory biomarkers (IL-1β, IL-6, IL-8, IL-10 significantly increased on the expression of anti-inflam - e TNF-α), cartilage degradation biomarker (CTX-II) and matory [interleukin-4 (IL-4) and interleukin-10 (IL- functional capacity (WOMAC) in patients with knee OA. 10)] biomarkers in the synovium of an OA-induced rat model. The exercise protocol has been shown to Materials and methods have an anti-inflammatory effect, reducing levels of Study design and setting biomarkers like IL-6 and TNFα and suggesting that This is a single-blind (participants) randomized con - cytokine reduction can be an effective contribution for trolled trial. Ethical approval (Ethics in Human modulating pain due to OA [13]. Research Committee of the Federal University of São V assão et al. Adv Rheumatol (2021) 61:62 Page 3 of 10 Paulo- approval number 1.368.478) and written informed A researcher, who was not involved in the experiment, consent (patients signed) were obtained. The study was conducted the randomization process by a simple draw- conducted at the Laboratory of Manual and Physical ing through a computer program that created a random Resources and Balance Space – Fitness and Health from table of numbers and put these numbers (1, 2 and 3) on April 2018 to February 2020 and was logged with the opaque envelopes corresponding the group (ESP, EAP Brazilian Clinical Trials Registry (RBR-7t6nzr). All par- and CG), respectively. ticipants were recruited via advertisements in local news- Evaluation and reevaluation were performed by a papers and social media. researcher blinded to the experimental groups. Patients were also blinded to the mode of PBM application (sham or active). Patients As eligibility criteria, patients had aged between 55 and 70  years, present symptomatic OA in the previous Sample size 6  months, a diagnosis of unilateral or bilateral knee OA The sample size calculation was performed using the according to the American College of Rheumatology and GPower 3.0.10 program with parameters: effects size of a radiographic confirmation of OA (grades 2 or 3 of the 0.25 [27], power observed of 0.75 and α = 5%, considering Kellgren-Lawrence classification) [25]. The diagnosis of ANOVA model for three groups. The required sample knee OA was determined through an examination and would be 12 patients for each treatment group ESP, EAP the written opinion of a specialist in rheumatic diseases. or CG with a total of 36 patients. Each treatment group Also, patients should present BMI between 22 to 35  kg/ was started with 14 patients for possible dropout. m , criteria established by Pan American Health Organi- zation [26], more than 2 points on the Numeric Rating Experimental procedures Pain Scale and should be classified as active and irregu - After the initial evaluation, the following experimental larly active (physical activity with a frequency of at least 3 procedures were made 48  h before and 48  h after inter- times a week or a minimum of 150 min per week, accord- ventions: blood collection and functional capacity anal- ing to Criteria established by American College of Sports ysis (WOMAC). Participants of the control group were Medicine measures by the International Physical Activity oriented to maintain the same habits and do not start any Questionnaire – Short Version (IPAQ). new treatment for the period of 8 weeks. Patients were excluded if they have: fibromyalgia and/ or any kind of orthopedic or rheumatic diseases that may Assessments prevent the physical exercise; surgery of the knee within WOMAC questionnaire the past 6  months or joint replacement. Also, patients The functional capacity of lower limb and knee joint with diagnoses of lung diseases, cardiologic altera- could be evaluated by using Western Ontario and tions, uncontrolled hypertension, diabetes and had any McMaster Universities Osteoarthritis (WOMAC). The contraindications to PBM as cancer. During the study, WOMAC is a self-administered reliable and valid ques- patients who missed two consecutive training sessions or tionnaire for patients with hip and knee OA and used for more than 3 sessions along the treatment and who dis- assessment of pain, stiffness joints, and physical activity continued the pharmacological treatment for OA started of patients with hip and knee OA [28, 29]. The total score before the study were excluded. range of 0–96 and increased scores indicate a higher level of disability and lower level of quality of life. Randomization All patients met all inclusion criteria to participate in the study and signed a consent form. 42 patients were ran- Blood collection and serum biomarkers measurement domly allocated in ESP, EAP or CG groups, as observed One biomedical collected 8  ml of peripheral blood sam- below: ples from each patient before and after intervention period. After collected, the samples were centrifuged ESP: exercise + sham PBM, patients of this group to prepare the plasma and stored at -80  °C in cryogenic performed the physical exercise program associated tubes until in measurement. All the samples were sent to to PBM sham irradiation; a certificate laboratory for analyses. The enzyme-linked EAP: exercise + active PBM, patients of this group immunosorbent assays (ELISA) kits were used to ana- performed the physical exercise program associated lyze the levels of CTX-II (MyBioSource), IL-1β and IL-10 to active PBM irradiation. (Enzo Life Sciences, Inc.) and IL-6, IL-8 e TNF-α (Fine CG: control group, patients of this group were not Test ) following the procedures recommended by the submitted to any kind of therapeutical intervention. manufacturer with automated pipetting. Vassão et al. Adv Rheumatol (2021) 61:62 Page 4 of 10 Interventions Both groups, ESP and EAP, received the intervention excepted CG (waitlist). Physical exercise program The physical exercise protocol used was adapted from the study by Silva et  al. [30] and Foley et  al., [31]. A protocol with warming (5 min on treadmill), 6 strength exercises (Hip abductors and adductors chair, SLR – seated leg raise, Glute Bridge (Hip lift), Knee flexors and extensors chair) and stretching of major muscle groups was used for this purpose. The patients were subjected to a physical exercise protocol twice a week (Monday and Wednesday) for 8 consecutive weeks performed individually and supervised by a physical therapist. The application of the physical exercise protocol occurred according to 1-RM (repetition maximum) was deter- mined each 2 weeks for prescription and load progres- sion of the exercises. The exercise consisted 3 sets of 8 Fig. 1 PBMT irradiation points repetitions each, with 60% of 1-RM and a rest interval of 2–3 min between sets based on American Geriatrics Society [32] for patients with OA. The difference between groups was performed per-pro - tocol analysis. PBM via cluster A cluster with 7 diodes and an infrared wavelength Results (808 nm) was used in continuous mode, a 0.05cm spot Six patients (one from ESP, one from EAP and four from size, 100mW power output, 2  W/cm power density, CG) were excluded from the study due to the absence in 91  J/cm energy density, and energy of 4  J per point/ 2 consecutive treatment sessions. Table  1 displays the 56  J per knee, 40  s per application based on recom- baseline values of the outcome measures, anthropomet- mendations of the World Association of Laser Therapy ric and demographic characteristics of the participants [33]. The cluster dimension is 150  mm(L) × 100  mm( per group. Significant difference among ESP (p = 0.024), W) × 55  mm(H), with 1  cm of distance between infra- EAP (p = 0.009) and CG were identified for age. The EAP red diodes. After each training session for ESP and group showed higher values of BMI compared to CG EAP, respectively, sham or active PBM was applied on (p = 0.04). The percentage of the weight range for each medial and lateral region of knee affected for unilateral group was 15.4% normal weight, 69.2% overweight and OA and applied on medial and lateral region of most 15.4% obesity for ESP; 30.8% normal weigh, 38.4% over affected knee for bilateral OA (with knee positioned at weight and 30.8% obesity for EAP and 50% normal weigh, 45 degrees of flexion) (Fig.  1). A researcher responsi- 40% overweight and 10% obesity for CG. ble to conduct the intervention turned on the device of Figure  2 shows the baseline and 8-week values of PBM irradiation and immediately turned off the equip - WOMAC total score. The results demonstrated that ment to apply the sham PBM. there was significant difference between ESP, in the baseline compared to ESP in the 8-week (p = 0.00006), between EAP in the baseline and EAP in the 8-week Statistical analysis (p = 0.00002) and between ESP and CG in the 8-week To analyze the variables age, height, body mass, BMI, (p = 0.011). IL-1β, IL-6, IL-8, IL-10, TNF-α, CTX-II and WOMAC at The results of WOMAC pain, stiffness and function groups and evaluations, were performed the analysis of subscales are demonstrated in Table 2. There was signifi variance (ANOVA one-way and two-way test) followed by cant decrease in all domains for ESP and EAP compared Fisher’s post hoc test to identify the possible differences baseline with 8-week evaluation (p < 0,05) and significant among groups. The adopted significant value was α < 5%. decrease in WOMAC stiffness subscale for CG (p = 0.01). Data were expressed as mean ± standard deviation (SD). u Th s, in baseline values, significant difference was found V assão et al. Adv Rheumatol (2021) 61:62 Page 5 of 10 Table 1 Mean and SD of baseline values, anthropometric and demographic characteristics Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Mean SD Mean SD Mean SD Age (years) 62.29 ± 4.39 * 61.57 ± 4.42 * 66.5 ± 4.06 Height (m) 1.60 ± 0.04 1.60 ± 0.07 1.60 ± 0.06 Body mass (kg) 77.06 ± 10.34 78.6 ± 12.67 69.9 ± 7.29 BMI (kg/m ) 30.11 ± 3.64 30.49 ± 4.35 * 27.24 ± 2.99 Unilateral and Bilateral OA (%) 23% uni 77% bi 23% uni 77% bi 50% uni 50% bi WOMAC pain 7.43 ± 3.48 10.36 ± 2.76 9.1 ± 4.33 WOMAC stiffness 3.21 ± 2.51 2.57 ± 1.55 3.2 ± 2.34 &, WOMAC function 23 ± 11.36 30.5 ± 7.79 * 21.3 ± 9.25 WOMAC total 33.64 ± 15.92 43.43 ± 9.89 33.6 ± 9.86 IL-10 (pg/ml) 8.52 ± 2.09 8 ± 2.48 7.21 ± 1.39 IL-1β (pg/ml) 5.02 ± 0.52 5.47 ± 1.16 4.98 ± 0.64 CTX-II (ng/ml) 4.24 ± 0.78 4.10 ± 1.10 4.45 ± 0.48 IL-6 (pg/ml) 5.66 ± 0.35 5.61 ± 0.68 5.34 ± 0.13 IL-8 (pg/ml) 11.28 ± 2.54 11.25 ± 1.77 11.26 ± 1.81 TNF-α (pg/ml) 26.94 ± 14.88 26.38 ± 20.01 19.68 ± 1.19 ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group; BMI: body mass index; kg: kilograms; m: meter; uni: unilateral; bi: bilateral. IL-10: interleukin-10; IL-1β: interleukin-1β; CTX-II: C-telopeptide of type II collagen; IL-8: interleukin-8; TNF-α: Tumor Necrosis Factor alpha; WOMAC: Western Ontario and McMaster Universities Osteoarthritis statistical difference from CG statistical difference from ESP in WOMAC pain (p = 0.02) and function (p = 0.01) sub- scales 8-week. Figure  3 shows the baseline and 8-week values of the IL-10. It is possible to observe a statistical significant dif - ference between the values found for EAP in the baseline compared to the 8-week (p = 0.047). Also, a significant difference was found between the values of EAP and CG after the experimental period (p = 0.0009). For IL-1β expression, there was a significant increase and difference between the values found in the baseline and in the 8-week for CG (p = 0.016) (Fig. 4). Table  3 shows the values found in the baseline and in the 8-week of the pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and cartilage degradation biomarkers (CTX- II). For these variables, no significant difference was observed. Fig. 2 Values of WOMAC in the baseline and in the 8-week for all the experimental groups. WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group. statistical Discussion significance between in the baseline and in the 8-week. Statistical The results of this study demonstrated that the physical significance from ESP group in the same condition exercise program was able of increasing the functional capacity in the patients and, the associated treatments increased IL-10 expression compared to CG after the experimental period. In addition, IL-1β expression was between the EAP and ESP in WOMAC pain (p = 0.04) higher for CG comparing the values in the baseline and and function (p = 0,0001) subscales, and between EAP 8-week and no difference for the others biomarkers were and CG in WOMAC function subscale (p = 0.02). Sig- observed. nificant difference was found between the ESP and CG Vassão et al. Adv Rheumatol (2021) 61:62 Page 6 of 10 Table 2 Means and SD of Western Ontario and McMaster Universities Osteoarthritis Questionnaire Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Baseline 8-week Baseline 8-week Baseline 8-week Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD a a WOMAC pain 7.43 ± 3.48 3.36 ± 2.87 * 10.36 ± 2.76 4.79 ± 4.51 * 9.1 ± 4.33 7 ± 4.27 WOMAC stiffness 3.21 ± 2.51 1.21 ± 1.48 * 2.57 ± 1.55 1.43 ± 1.28 * 3.2 ± 2.35 1.7 ± 1.7 * a b a WOMAC function 23 ± 11.36 9.5 ± 7.38 * 30.5 ± 7.79 16.14 ± 10.7 * 21.3 ± 9.25 19.8 ± 11.45 WOMAC total score 33.64 ± 15.92 14.07 ± 10.99* 43.43 ± 9.89 22.36 ± 15.49* 33.60 ± 9.86 28.50 ± 15.95 ESP exercise and sham PBM group, EAP exercise and active PBM group, CG control group, WOMAC: Western Ontario and McMaster Universities Osteoarthritis statistical significance between in the baseline and in the 8-week statistical significance from ESP group in the same condition statistical significance from EAP group in the same condition Fig. 3 Values of IL-10 concentration in the baseline and in the 8-week for all the experimental groups. IL-10: interleukin-10; ESP: exercise and Fig. 4 Values of IL-1β concentration baseline and 8-week for all sham PBM group; EAP: exercise and active PBM group; CG: control the experimental groups. IL-1ß: interleukin-1ß; ESP: exercise and group. statistical significance between in the baseline and 8-week sham PBM group; EAP: exercise and active PBM group; CG: control values. statistical significance between in the 8-week values * group. Statistical significance between in the baseline and 8-week intervention values Knee OA is clinically associated with pain and loss of functional capacity, reaching 25% of the population with OA treated with physical exercises and PBM. One over the age of 60  years [34]. As described above, the hypothesis that can be raised is that the PBM param- lower WOMAC score demonstrated by the physical eters used in this study were not sufficient to produce exercised patients (irradiated or not with PBM) is pos- an additional effect in the exercised patients. sibly related to the increase in muscle strength after the Furthermore, it is well known that IL-10 has an exercise program, improving the joint stability and the important anti-inflammatory role in OA, presenting a level of pain, and consequently, leading to the improve- chondroprotective effect and, inhibiting chondrocyte ment of the functional capacity. Interestingly, PBM did apoptosis [38]. Our results showed that the active PBM not produce any extra positive effect in the exercised associated with physical exercises significantly increased patients. Data from the literature do not corroborate IL-10 expression after the experimental period of treat- the findings of the present study demonstrating a supe - ment. Assis et al., [17] also observed an increase of IL-10 rior effect measured by WOMAC in exercised and irra - expression in an experimental study, submitting rats with diated patients with OA [35–37]. Kheshie et al. [36] also OA to a program of aerobic exercises and PBM irradia- observed a decrease in WOMAC subscales in patients tion. All the positive effects may be related to the effects V assão et al. Adv Rheumatol (2021) 61:62 Page 7 of 10 Table 3 Means and SD of IL-10, IL-1b, IL-6, IL-8, TNF-α and CTX-II Variables ESP (n = 13) EAP (n = 13) CG (n = 10) Baseline 8-week Baseline 8-week Baseline 8-week Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD IL-10 (pg/ml) 8.52 ± 2.09 8.44 ± 2.33 8.00 ± 2.48 9.98 ± 3.42*& 7.21 ± 1.39 6.54 ± 0.63 IL-1b (pg/ml) 5.02 ± 0.52 4.94 ± 0.49 5.47 ± 1.16 5.11 ± 0.92 4.98 ± 0.64 5.67 ± 1.99* CTX II (ng/ml) 4.24 ± 0.78 4.38 ± 0.63 4.10 ± 1.10 4.26 ± 0.65 4.45 ± 0.48 4.07 ± 0.98 IL-6 (pg/ml) 5.66 ± 0.35 5.57 ± 0.24 5.61 ± 0.68 5.65 ± 0.86 5.34 ± 0.13 5.37 ± 0.22 IL-8 (pg/ml) 11.28 ± 2.54 11.76 ± 2.97 11.25 ± 1.77 11.40 ± 1.73 11.26 ± 1.81 11.89 ± 1.85 TNF-α (pg/ml) 26.94 ± 14.88 26.24 ± 12.11 26.38 ± 20.01 23.00 ± 8.59 19.68 ± 1.19 19.42 ± 1.09 statistical significance between in the baseline and 8-week values statistical significance between in the 8-week values compare to CG group ESP: exercise and sham PBM group; EAP: exercise and active PBM group; CG: control group of physical exercises and PBM on inflammatory mark - inflammatory cytokine IL-6 in OA animals [46]. How - ers. Physical exercises (and the related muscle contrac- ever, experimental studies indicate that PBM is capable of tion) produce a mechanotransduction stimulus, which modulating inflammatory mediators such as IL-6 in rats maintain homeostasis of articular cartilage and con- using an experimental model of joint inflammation [47]. tribute to attenuate OA physiological events [39]. As a The controversial results may be related to PBM param - consequence, physical exercise programs have anabolic, eters or the frequency if the treatment. anti-inflammatory and antioxidant effects in OA patients Furthermore, both treatments did not have any effect [40]. Moreover, many studies have demonstrated the on IL-8 and TNF-α cytokines concentration. IL-8 is anti-inflammatory effects of PBM [41, 42]. PBM is able to a chemokine produced by various inflammatory cells modulate mRNA gene expression of IL-10 in acute and such as neutrophils, basophils, macrophages and T cells chronic inflammatory phase and decreases the expres - [48]. TNF-α, a pro-inflammatory cytokine seems to be sion of this cytokine and consequently modulates the related to IL-1β (pro-inflammatory cytokine) because inflammatory process of OA [43]. Taking together, the are secreted by the same cells of the joint, in addition the combined treatments presented a positive effect on IL-10 increased presence of TNF-α stimulates the synthesis of expression, which could represent a modulation of the IL-6 and IL-8 [49]. These results corroborates with Hel - inflammatory process. mark et al., [50] who also observed that a resistance exer- IL-1β is considered one of the main cytokines in OA cise training (25 sets of 10 repetitions at 60% of 1-RM) development and the literature points out that the reduc- have not decreased the levels of IL-8 and IL-6 of patients tion of IL-1β production is an indication of the attenua- with knee OA. Aguiar et  al., [13] have not observed tion of cartilage degenerative process related to OA [44]. changes in TNF-α expression after 12  weeks of physi- CG demonstrated a significant increase of IL-1β expres - cal training using 60–80% of the maximum load of indi- sion after the experimental period. Similarly, an experi- viduals with knee OA. In addition, a study applied PBM mental study using rats with OA also observed a higher immediately after total knee arthroplasty and observed IL-1β expression in the control animals compared to the a decrease of IL-8 expression [49]. Moreover, a system- treated ones CG [45]. In this context, it can be suggested atic review and meta-analysis points out that the PBM that the treatments were able to positively kept stable the is capable of reduce considerably TNF-α expression in IL-1β expression. models of joint inflammation [47]. The results of the pre - IL-6, a pro-inflammatory cytokine has a catabolic sent study for IL-8 and TNF-α cytokines can be justified activity in the pathogenesis of OA. In the present study, by type and modality of the load used in physical exer- no significant difference in IL-6 expression was observed cises once it is suggested that maximum training load in both experimental periods for any group. Conversely, seems to modulate the levels of these cytokine [51]. Aguiar et  al., [13] found a significant reduction in IL-6 CTX-II is a biomarker released due to the degenera- levels in patients with knee OA, after a treatment of flex - tion of cartilage related to catabolic activity that leads to ibility training and muscle strengthening, 3 times a week loss of type II collagen concentration, which is the most for 12  weeks. Furthermore, a systematic review con- abundant protein of the cartilage matrix and proteogly- cluded that PBM has no effect on the expression of the can matrix of cartilage [52]. There was no statistically Vassão et al. Adv Rheumatol (2021) 61:62 Page 8 of 10 significant difference in CTX-II levels in this study. These • Physical exercise program and its association with findings do not corroborate those of with Nambi et  al. PBM had no effect on others pro-inflammatory and [1], which demonstrated that a protocol of PBM (905 nm, cartilage degradation biomarkers. super pulsed, 1.5 J per point, 12 J per knee) and exercise in patients with knee OA during 4 weeks (twice a week) were able of inhibiting CTX-II, MMP-3 (stromelysin), MMP-8 (collagenase-2), and MMP-13 (collagenase-3) Abbreviations expression. However, the study mentioned analyse the OA: Osteoarthritis; TNF-α: Tumor Necrosis Factor alpha; IL-1β: Interleukin-1β; levels of CTX-II fragments from urinary fraction and our IL-6: Interleukin -6; MMPs: Matrix metalloproteinases; CTX-II: C-telopeptide of type II collagen; NSAIDs: Nonsteroidal and steroidal anti-inflammatory study evaluated from the serum fraction of peripheral drugs; MPA: Moderate physical activity; ILs: Interleukins; LLLT: Low-level laser blood samples and this difference in analyse can justify therapy; PBM: Photobiomodulation; WOMAC: Western Ontario and McMaster the results of the present study. Universities Arthritis Index; LED: Light-emitting diode; ESP: Exercise sham pho- tobiomodulation group; EAP: Exercise active photobiomodulation group; CG: In addition, it may be suggested that PBM applica- Control group; ANOVA: Analysis of variance; ELISA: Enzyme-linked immuno- tion, through a cluster device constitutes an advantage sorbent assays; SLR: Seated leg raise; RM: Repetition maximum. for treating patients with knee OA, allowing the irradia- Acknowledgements tion of a larger area and optimizing the treatment [21]. Not applicable. Although some positive effects of the treatments in the patients in this study, some limitations can be raised as Authors’ contributions PGV, HTT and ACR–Conceptualization, methodology, data collection, writing- a minor number of patients in sample size. It would be original draft preparation and editing; RMDSC and LAG–methodology, statistic extremely important to assess the presence of inflamma - work, writing-reviewing and editing. CFDS—biomedicine responsible for tory markers in the synovial fluid, which would increase blood sample collection from volunteers. The author(s) read and approved the final manuscript. the accuracy of their analysis, as well as the possibility of correlating them with symptomatic variables. Also, there Funding is an absence of a follow-up in order to provide informa- This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo – 2016/08503–0. tion about the maintenance of results over time in these patients. Availability of data and materials Study data can be made available upon reasonable request to the principal investigator. Conclusion The results of this study demonstrated that the physical Declarations exercise program in association with PBM was capable of increasing IL-10 levels, and the physical exercise pro- Ethics approval and consent to participate All procedures were approved by the Ethics Committee of University gram improved the function capacity. However, PBM did (Approval Number 1368478) and, registered in www. clini caltr ials. gov, RBR- not promote an additional effect to the positive effects 7t6nzr. All participants gave their informed consent before participation. of exercise in improving pro-inflammatory and carti - Consent for publication lage degradation biomarkers, and functional capacity in Not applicable. women with knee OA. Thus, more studies need to be carried out, using other parameters, since the literature Competing interests The author(s) declare(s) that there is no conflict of interest. demonstrates heterogeneity in the parameters of treat- ment with PBM when associated with physical exercise, Author details for the consolidation of an intervention protocol for Department of Biosciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Depar tment patients with knee OA. of Human Movement Science, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Post Grad- Clinical messages uate Program of Interdisciplinary Health Sciences, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136, Santos, SP 11015-020, Brazil. Scientific Institute and Technological Department -University Brazil, São • Patients who underwent physical exercise program in Paulo-Itaquera, SP, Brazil. association with PBM for 8  weeks showed improve- Received: 14 June 2021 Accepted: 5 October 2021 ment in IL-10 levels after treatment and when com- pared to the control group who did not any interven- tion; • The function capacity was improved in patients References undergoing a physical exercise program; 1. S GN, Kamal W, George J, Manssor E. Radiological and biochemical effects • Only the control group had the pro-inflammatory (CTX-II, MMP-3, 8, and 13) of low-level laser therapy (LLLT ) in chronic oste- oarthritis in Al-Kharj, Saudi Arabia. Lasers Med Sci. 2017; 32(2):297–303. marker (IL-1β) increased; V assão et al. Adv Rheumatol (2021) 61:62 Page 9 of 10 2. Duan ZX, Huang P, Tu C, Liu Q, Li SQ, Long ZL, Li ZH. MicroRNA-15a-5p 19. Soleimanpour H, Gahramani K, Taheri R, Golzari SE, Safari S, Esfanjani RM, regulates the development of osteoarthritis by targeting PTHrP in chon- Iranpour A. The effect of low-level laser therapy on knee osteoarthritis: drocytes. Biomed Res Int. 2019;2019(5):3904923. https:// doi. org/ 10. 1155/ prospective, descriptive study. Lasers Med Sci. 2014;29(5):1695–700. 2019/ 39049 23.https:// doi. org/ 10. 1007/ s10103- 014- 1576-6. 3. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The role of inflammatory 20. Alghadir A, Omar MT, Al-Askar AB, Al-Muteri NK. Eec ff t of low-level laser and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. therapy in patients with chronic knee osteoarthritis: a single-blinded Mediators Inflamm. 2014;2014: 561459. https:// doi. org/ 10. 1155/ 2014/ randomized clinical study. Lasers Med Sci. 2014;29(2):749–55. https:// doi. 561459.org/ 10. 1007/ s10103- 013- 1393-3. 4. Al-Khazraji BK, Appleton CT, Beier F, Birmingham TB, Shoemaker JK. 21. de Paula Gomes CAF, Leal-Junior ECP, Dibai-Filho AV, de Oliveira AR, Bley Osteoarthritis, cerebrovascular dysfunction and the common denomi- AS, Biasotto-Gonzalez DA, de Tarso Camillo de Carvalho P. Incorporation nator of inflammation: a narrative review. Osteoarthritis Cartilage. of photobiomodulation therapy into a therapeutic exercise program for 2018;26(4):462–70. https:// doi. org/ 10. 1016/j. joca. 2018. 01. 011. knee osteoarthritis: A placebo-controlled, randomized, clinical trial. Lasers 5. Tomazoni SS, Frigo L, Dos Reis Ferreira TC, Casalechi HL, Teixeira S, de Surg Med 2018; 50(8):819–828. doi: https:// doi. org/ 10. 1002/ lsm. 22939. Almeida P, Muscara MN, Marcos RL, Serra AJ, de Carvalho PTC, Leal-Junior 22. Alfredo PP, Bjordal JM, Junior WS, Lopes-Martins RÁB, Stausholm MB, ECP. Eec ff ts of photobiomodulation therapy and topical non-steroidal Casarotto RA, Marques AP, Joensen J. Long-term results of a randomized, anti-inflammatory drug on skeletal muscle injury induced by contusion controlled, double-blind study of low-level laser therapy before exercises in rats-part 1: morphological and functional aspects. Lasers Med Sci. in knee osteoarthritis: laser and exercises in knee osteoarthritis. Clin 2017;32(9):2111–20. https:// doi. org/ 10. 1007/ s10103- 017- 2346-z. Rehabil. 2018;32(2):173–8. https:// doi. org/ 10. 1177/ 02692 15517 723162. 6. Nefla M, Holzinger D, Berenbaum F, Jacques C. The danger from within: 23. Alayat MSM, Atya AM, Ali MME, Shousha TM. Correction to: Long-term alarmins in arthritis. Nat Rev Rheumatol. 2016;12(11):669–83. https:// doi. effect of high-intensity laser therapy in the treatment of patients with org/ 10. 1007/ s10103- 017- 2346-z. chronic low back pain: a randomized blinded placebo-controlled trial. 7. Severino RM, Jorge PB, Martinelli MO, deLima MV, Severino NR, Duarte Lasers Med Sci. 2020;35(1):297. https:// doi. org/ 10. 1007/ s10103- 019- Junior A. Analysis on the serum levels of the biomarker CTX-II in profes-02926-x. Errat umfor: Laser sMedS ci. 20142 9(3): 1065- 73. sional indoor soccer players over the course of one season. Rev Bras 24. de Matos Brunelli Braghin R, Libardi EC, Junqueira C, Rodrigues NC, Ortop. 2015;50(3):331–5. https:// doi. org/ 10. 1016/j. rboe. 2015. 04. 001. Nogueira-Barbosa MH, Renno ACM, Carvalho de Abreu DC. The effect of 8. Saberi Hosnijeh F, Siebuhr AS, Uitterlinden AG, Oei EH, Hofman A, Karsdal low-level laser therapy and physical exercise on pain, stiffness, function, MA, Bierma-Zeinstra SM, Bay-Jensen AC, van Meurs JB. Association and spatiotemporal gait variables in subjects with bilateral knee osteoar- between biomarkers of tissue inflammation and progression of osteo - thritis: a blind randomized clinical trial. Disabil Rehabil 2019; 41(26):3165– arthritis: evidence from the Rotterdam study cohort. Arthritis Res Ther. 3172. doi: https:// doi. org/ 10. 1080/ 09638 288. 2018. 14931 60. 2016;1(18):81. https:// doi. org/ 10. 1186/ s13075- 016- 0976-3. 25. Kellgren JH, Lawrence JS. Radiological assessment of rheumatoid arthritis. 9. Rannou F. [Prescribe non-pharmacological treatments for lower limb Ann Rheum Dis. 1957;16:485–93. osteoarthritis?]. Rev Prat 2012; 62(5):651–3. Review. French. 26. Organización Panamericana de la Salud. XXXVI Reunión del Comité Ase- 10. Wyszyńska J, Bal-Bocheńska M. Efficacy of high-intensity laser therapy sor de Investigaciones en Salud. Encuesta Multicéntrica: Salud Bienestar in treating knee osteoarthritis: a first systematic review. Photomed Laser y Envejecimiento (SABE) en América Latina y el Caribe [Internet]. 2011 Surg. 2018;36(7):343–53. https:// doi. org/ 10. 1089/ pho. 2017. 4425. Washington, D.C: Organización Panamericana de la Salud; Disponível em: 11. Bennell KL, Hall M, Hinman RS. Osteoarthritis year in review 2015: rehabili-http:// envej ecimi ento. csic. es/ docum entos/ docum entos/ paho- salud- 01. tation and outcomes. Osteoarthritis Cartilage. 2016;24(1):58–70. https:// pdf doi. org/ 10. 1016/j. joca. 2015. 07. 028. 27. » http:// envej ecimi ento. csic. es/ docum entos/ docum entos/ paho- salud- 12. Castrogiovanni P, Di Rosa M, Ravalli S, et al. Moderate physical activity as a 01. pdf prevention method for knee osteoarthritis and the role of synoviocytes as 28. Abd El-Kader SM, Al-Shreef FM, Al-Jiffri OH. Impact of aerobic exercise biological key. Int J Mol Sci. 2019;20(3):511. https:// doi. org/ 10. 3390/ ijms2 versus resisted exercise on endothelial activation markers and inflamma- 00305 11. tory cytokines among elderly. Afr Health Sci. 2019;19(4):2874–80. https:// 13. Aguiar GC, Do Nascimento MR, De Miranda AS, Rocha NP, Teixeira AL, doi. org/ 10. 4314/ ahs. v19i4.9. Scalzo PL. Eec ff ts of an exercise therapy protocol on inflammatory mark - 29. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Valida- ers, perception of pain, and physical performance in individuals with tion study of WOMAC: a health status instrument for measuring knee osteoarthritis. Rheumatol Int. 2015;35(3):525–31. https:// doi. org/ 10. clinically important patient relevant outcomes to antirheumatic drug 1007/ s00296- 014- 3148-2. therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 14. Assis L, Milares LP, Almeida T, Tim C, Magri A, Fernandes KR, Medalha C, 1988;15(12):1833–40. Muniz Renno AC. Aerobic exercise training and low-level laser therapy 30. Choquette D, Bellamy N, Raynauld JP. A French-Canadian version of the modulate inflammatory response and degenerative process in an WOMAC osteoarthritis index. Arthritis Rheum. 1994;37:S226. experimental model of knee osteoarthritisin rats. Osteoarthr Cartil. 31. Silva LE, Valim V, Pessanha AP, Oliveira LM, Myamoto S, Jones A, Natour J. 2016;24:169–77. https:// doi. org/ 10. 1007/ s00296- 014- 3148-2. Hydrotherapy versus conventional land-based exercise for the manage- 15. Balbinot G, Schuch CP, Nascimento PSD, Lanferdini FJ, Casanova M, ment of patients with osteoarthritis of the knee: a randomized clinical Baroni BM, Vaz MA. Photobiomodulation therapy partially restores trial. Phys Ther. 2008;88:12–21. https:// doi. org/ 10. 2522/ ptj. 20060 040. cartilage integrity and reduces chronic pain behavior in a rat model 32. Foley A, Halbert J, Hewitt T, Crotty M. Does hydrotherapy improve of osteoarthritis: involvement of spinal glial modulation. Cartilage. strength and physical function in patients with osteoarthritis–a ran- 2019;30:1947603519876338. https:// doi. org/ 10. 1177/ 19476 03519 876338. domised controlled trial comparing a gym based and a hydrotherapy 16. Hamblin MR. Mechanisms and applications of the anti-inflammatory based strengthening programme. Ann Rheum Dis. 2003;62:1162–7. effects of photobiomodulation. AIMS Biophys. 2017;4(3):337–61. https:// https:// doi. org/ 10. 1136/ ard. 2002. 005272. doi. org/ 10. 3934/ biophy. 2017.3. 337. 33. American Geriatrics Society Panel on Exercise and Osteoarthritis. Exercise 17. Assis L, Tim C, Magri A, Fernandes KR, Vassão PG, Renno ACM. Inter- prescription for older adults with osteoarthritis pain: consensus practice leukin-10 and collagen type II immunoexpression are modulated by recommendations. A supplement to the AGS Clinical Practice Guide- photobiomodulation associated to aerobic and aquatic exercises in an lines on the management of chronic pain in older adults. J Am Geriatr experimental model of osteoarthritis. Lasers Med Sci. 2018;33(9):1875–82. Soc 2001; 49(6):808–823 Review. Erratum in: J Am Geriatr Soc 2001 https:// doi. org/ 10. 1007/ s10103- 018- 2541-6. Oct;49(10):1400 18. de Oliveira VL, Silva JA Jr, Serra AJ, Pallotta RC, da Silva EA, de Farias 34. World Association of Laser Therapy ( WALT ). Consensus agreement on the Marques AC, Feliciano RD, Marcos RL, Leal-Junior EC, de Carvalho PT. design and conduct of clinical studies with low- level laser therapy and Photobiomodulation therapy in the modulation of inflammatory light therapy for musculoskeletal pain and disorders. Photomed Laser mediators and bradykinin receptors in an experimental model of acute Surg. 2006;24:761–2. osteoarthritis. Lasers Med Sci. 2017;32(1):87–94. https:// doi. org/ 10. 1007/ 35. Alcalde GE, Fonseca AC, Bôscoa TF, et al . Eec ff t of aquatic physical s10103- 016- 2089-2. therapy on pain perception, functional capacity and quality of life in Vassão et al. Adv Rheumatol (2021) 61:62 Page 10 of 10 older people with knee osteoarthritis: study protocol for a randomized 45. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of controlled trial. Trials 2017; 18(1):317. Published 2017 Jul 11. doi:https:// proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat doi. org/ 10. 1186/ s13063- 017- 2061-x. Rev Rheumatol. 2011;7(1):33–42. https:// doi. org/ 10. 1038/ nrrhe um. 2010. 36. Alfredo PP, Bjordal JM, Dreyer SH, Meneses SR, Zaguetti G, Ovanessian 196. V, Fukuda TY, Junior WS, Lopes Martins RÁ, Casarotto RA, Marques AP. 46. Sanches M, Assis L, Criniti C, Fernandes D, Tim C, Renno ACM. Chondroi- Efficacy of low level laser therapy associated with exercises in knee osteo - tin sulfate and glucosamine sulfate associated to photobiomodulation arthritis: a randomized double-blind study. Clin Rehabil. 2012;26:523–33. prevents degenerative morphological changes in an experimental model https:// doi. org/ 10. 1016/ S2255- 4971(15) 30407-9. of osteoarthritis in rats. Lasers Med Sci. 2018;33(3):549–57. https:// doi. 37. Kheshie AR, Alayat MS, Ali MM. High-intensity versus low-level laser ther-org/ 10. 1007/ s10103- 017- 2401-9. apy in the treatment of patients with knee osteoarthritis: a randomized 47. Nambi G. Does low level laser therapy has effects on inflammatory bio - controlled trial. Lasers Med Sci. 2014;29(4):1371–6. https:// doi. org/ 10. markers IL-1β, IL-6, TNF-α, and MMP-13 in osteoarthritis of rat models-a 1007/ s10103- 014- 1529-0. systemic review and meta-analysis. Lasers Med Sci. 2021;36(3):475–84. 38. Nazari A, Moezy A, Nejati P, Mazaherinezhad A. Efficacy of high-intensity https:// doi. org/ 10. 1007/ s10103- 020- 03124-w. laser therapy in comparison with conventional physiotherapy and exer- 48. Alves AC, Vieira R, Leal-Junior E, dos Santos S, Ligeiro AP, Albertini R, Junior cise therapy on pain and function of patients with knee osteoarthritis: J, de Carvalho P. Eec ff t of low-level laser therapy on the expression of a randomized controlled trial with 12-week follow up. Lasers Med Sci. inflammatory mediators and on neutrophils and macrophages in acute 2019;34(3):505–16. https:// doi. org/ 10. 1007/ s10103- 018- 2624-4. joint inflammation. Arthritis Res Ther. 2013;15(5):R116. https:// doi. org/ 10. 39. Kwon JY, Lee SH, Na HS, Jung K, Choi J, Cho KH, Lee CY, Kim SJ, Park 1186/ ar4296. SH, Shin DY, Cho ML. Kartogenin inhibits pain behavior, chondrocyte 49. Hoff P, Buttgereit F, Burmester GR, Jakstadt M, Gaber T, Andreas K, inflammation, and attenuates osteoarthritis progression in mice through Matziolis G, Perka C, Röhner E. Osteoarthritis synovial fluid activates induction of IL-10. Sci Rep. 2018; 14;8(1):13832. doi: https:// doi. org/ 10. pro-inflammatory cytokines in primary human chondrocytes. Int Orthop. 1038/ s41598- 018- 32206-7. 2013;37(1):145–51. https:// doi. org/ 10. 1007/ s00264- 012- 1724-1. 40. Bader DL, Salter DM, Chowdhury TT. Biomechanical influence of car - 50. Langella LG, Casalechi HL, Tomazoni SS, Johnson DS, Albertini R, Pallotta tilage homeostasis in health and disease. Arthritis. 2011;2011:979032. RC, Marcos RL, de Carvalho PTC, Leal-Junior ECP. Photobiomodula- doi: https:// doi. org/ 10. 1155/ 2011/ 979032. Epub 2011 Sep 15. PMID: tion therapy (PBMT ) on acute pain and inflammation in patients who 22046527; PMCID: PMC3196252. underwent total hip arthroplasty-a randomized, triple-blind, placebo- 41. Cifuentes DJ, Rocha LG, Silva LA, Brito AC, Rueff-Barroso CR, Porto LC, controlled clinical trial. Lasers Med Sci. 2018;33(9):1933–40. https:// doi. Pinho RA. Decrease in oxidative stress and histological changes induced org/ 10. 1007/ s10103- 018- 2558-x. by physical exercise calibrated in rats with osteoarthritis induced by 51. Helmark IC, Mikkelsen UR, Børglum J, Rothe A, Petersen MC, Andersen monosodium iodoacetate. Osteoarthritis Cartilage. 2010;18(8):1088–95. O, Langberg H, Kjaer M. Exercise increases interleukin-10 levels both https:// doi. org/ 10. 1016/j. joca. 2010. 04. 004. intraarticularly and peri-synovially in patients with knee osteoarthritis: a 42. Pigatto GR, Silva CS, Parizotto NA. Photobiomodulation therapy reduces randomized controlled trial. Arthritis Res Ther. 2010;12(4):R126. https:// acute pain and inflammation in mice. J Photochem Photobiol B. doi. org/ 10. 1186/ ar3064. 2019;196: 111513. https:// doi. org/ 10. 1016/j. jphot obiol. 2019. 111513. 52. Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF. Resistance 43. Li K, Liang Z, Zhang J, Zuo X, Sun J, Zheng Q, Song J, Ding T, Hu X, Wang exercise decreases skeletal muscle tumor necrosis factor alpha in frail Z. Attenuation of the inflammatory response and polarization of mac- elderly humans. FASEB J. 2001;15(2):475–82. https:// doi. org/ 10. 1096/. fj 00- rophages by photobiomodulation. Lasers Med Sci. 2020;35(7):1509–18. 0274c om. https:// doi. org/ 10. 1007/ s10103- 019- 02941-y. 44. Casalechi HL, Leal-Junior EC, Xavier M, Silva JA Jr, de Carvalho PD, Publisher’s Note Aimbire F, Albertini R. Low-level laser therapy in experimental model Springer Nature remains neutral with regard to jurisdictional claims in pub- of collagenase-induced tendinitis in rats: effects in acute and chronic lished maps and institutional affiliations. inflammatory phases. Lasers Med Sci. 2013;28(3):989–95. https:// doi. org/ 10. 1007/ s10103- 012- 1189-x. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Journal

Advances in RheumatologySpringer Journals

Published: Oct 16, 2021

Keywords: Knee osteoarthritis; Inflammation; Cytokines; Biomarkers; Photobiomodulation

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