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Periostin expression in neoplastic and non-neoplastic diseases of bone and joint

Periostin expression in neoplastic and non-neoplastic diseases of bone and joint Background: Periostin is a matricellular protein that is expressed in bone and joint tissues. To determine the expres- sion of periostin in primary bone tumours and to assess whether it plays a role in tumour progression, we carried out immunohistochemistry and ELISA for periostin in a range of neoplastic and non-neoplastic bone and joint lesions. Methods: 140 formalin-fixed paraffin-embedded sections of bone tumours and tumour-like lesions were stained by an indirect immunoperoxidase technique with a polyclonal anti-periostin antibody. Periostin expression was also assessed in rheumatoid arthritis (RA) and non-inflammatory osteoarthritis (OA) synovium and synovial fluid immuno - histochemistry and ELISA respectively. Results: Periostin was most strongly expressed in osteoid/woven bone of neoplastic and non-neoplastic bone- forming lesions, including osteoblastoma, osteosarcoma, fibrous dysplasia, osteofibrous dysplasia, fracture callus and myositis ossificans, and mineralised chondroid matrix/woven bone in chondroblastoma and clear cell chondrosar - coma. Reactive host bone at the edge of growing tumours, particularly in areas of increased vascularity and fibrosis, also stained strongly for periostin. Vascular elements in RA synovium strongly expressed periostin, and synovial fluid levels of periostin were higher in RA than OA. Conclusions: In keeping with its known role in modulating the synthesis of collagen and other extracellular matrix proteins in bone, strong periostin expression was noted in benign and malignant lesions forming an osteoid or oste- oid-like matrix. Periostin was also noted in other bone tumours and was found in areas of reactive bone and increased vascularity at the edge of growing tumours, consistent with its involvement in tissue remodelling and angiogenesis associated with tumour progression. Keywords: Periostin expression, Bone tumours, Tumour progression Background matrix (ECM) proteins [3–6]. Periostin has a multi- Periostin, a secreted extracellular matrix protein that domain structure in which particular domains bind to belongs to the fasciclin family, was originally character- many proteins and enzymes that promote ECM protein ised in osteoblasts and first termed osteoblast-specific crosslinking. Periostin is involved in the formation and factor 2 [1, 2]. Periostin is a matricellular protein that maintenance of normal bone and teeth tissues and is does not have a specific structural role but rather inter - highly expressed in tissue components that are subject to mechanical stress, such as the periosteum and the acts with cell surface receptors, proteases and other periodontal ligament. It has also been observed in other molecules that modulate cell adhesion/migration and organs and tissues including heart, breast, lung, thyroid, the fibrillogenesis of collagen and other extracellular skin, placenta and ovary [3–6]. Periostin is expressed at sites of injury/repair and *Correspondence: nick.athanasou@ndorms.ox.ac.uk inflammation [ 3, 6, 7]. It has been identified in rheu 1 - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Sciences, Nuffield Orthopaedic Centre, matoid arthritis (RA) and osteoarthritis (OA) joints University of Oxford, Oxford OX3 7HE, UK [8, 9] with a recent study identifying periostin as a key Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 2 of 8 regulator in RA synoviocyte migration/invasion asso- Table 1 Bone tumours/tumour-like lesions analysed in this study ciated with pannus formation [10]. Periostin is also expressed in a number of cancers where it is thought, by Tissue type Number various mechanisms, to play a role in tumour progression analysed [3, 6, 11, 12]. Periostin has been identified in a few bone Osteoma 2 tumours, including fibrous dysplasia and osteosarcoma Osteoid osteoma 4 [13–15], but its expression in other bone neoplasms has Osteoblastoma 6 not been fully investigated. Osteosarcoma, conventional 20 In this study we investigated immunophenotypic Osteosarcoma, telangiectatic 2 expression of periostin in a wide range of primary Osteosarcoma, small cell 2 tumours and tumour-like lesions of bone as well as in Osteosarcoma, parosteal 2 bone secondaries and metastatic osteosarcomas. Our Fibrous dysplasia 10 aims were two-fold: first, to determine whether periostin Osteofibrous dysplasia 2 expression is increased in specific bone tumour types; Fracture 2 and second, to examine whether periostin plays a role in Myositis ossificans 2 tumour progression. Enchondroma 3 Chondroblastoma 9 Methods Chondromyxoid fibroma 3 Neoplastic and non‑neoplastic tissue samples analysed Chondrosarcoma, conventional 20 Tissue samples from 140 biopsies or surgical resections Chondrosarcoma, clear cell 5 of bone tumours and tumour-like lesions, were retrieved Giant cell tumour of bone 8 from the files of the Nuffield Orthopaedic Centre, His - Aneurysmal bone cyst 4 topathology Department, Oxford (Table  1). Criteria for Solitary bone cyst 2 the histological diagnosis of bone and joint lesions inves- Non-ossifying fibroma 3 tigated in this study were those of the 2013 WHO Clas- Undifferentiated pleomorphic sarcoma 3 sification of Tumours of Soft Tissue and Bone [16]. The Ewing sarcoma 6 tissues were fixed in 10% buffered formalin and, where Adamantinoma of long bone 1 necessary, decalcified in 5% nitric acid or EDTA. In addi - Chordoma 2 tion, formalin-fixed paraffin-embedded sections of syno - Plasma cell myeloma 2 vial tissue derived from patients with RA (n = 21) and Lymphoma 2 OA (n = 19) were examined. Samples of normal bone and Langerhans cell histiocytoma 2 joint tissues from amputation specimens of individuals Metastatic breast carcinoma 3 with no history or evidence of joint disease or neoplasia Metastatic melanoma 1 were used as controls. Synovial fluid (SF) was also aspi - rated from the knee joint of nine patients with OA and nine patients with RA. Ethics approval was obtained from the National Research Ethical Committee, and patient (enzyme-linked immunosorbent assay). The periostin consent was acquired prior to the collection of samples. concentration was assessed using a Human periostin/ OSF-2 ELISA kit (Adiopo bioscience, Santa Clara, CA, Immunohistochemistry for periostin USA). Statistical evaluation was performed using the Immunohistochemical staining for periostin was carried Mann–Whitney U test with p values less than 0.05 con- out by an indirect immunoperoxidase technique (without sidered as statistically significant. any antigen retrieval procedure) using a polyclonal rab- bit antiserum against human periostin raised by using Results peptide DNLDSDIRRGLESNVN (representing aminoac- Periostin expression in normal bone and joint tissues ids 143–158 of human periostin) as an immunogen [13, In normal bone there was strong expression of peri- 17]. As in previous studies [17], the antibody dilution was ostin in collagenous fibrous tissue of the periosteum. At 1:250 and sections of normal skin were employed as a points of tendon or ligament insertion into bone, strong positive control. periostin staining was also seen within collagenous tis- sue. There was no staining for periostin in normal lamel - lar cortical and cancellous bone, and osteocytes, bone Periostin expression in OA and RA synovial fluid lining cells, osteoblasts and osteoclasts did not express A quantitative measure of the level of periostin in knee periostin. Fatty and hematopoietic marrow was generally joint RA and OA synovial fluid was determined by ELISA Brown et al. Clin Sarcoma Res (2018) 8:18 Page 3 of 8 negative for periostin but, in some specimens, staining the matrix in areas of tumor cell proliferation. There was for periostin was noted in small sinusoidal vascular chan- strong staining for periostin in fibrous dysplasia and oste - nels within the marrow. In normal joints, the synovium ofibrous dysplasia, predominantly in the cellular fibrous and hyaline articular cartilage did not stain for periostin. stroma between bone trabeculae (Fig. 1f ). There was no specific staining of the chondroid matrix Periostin expression in tumours and tumour‑like lesions or cartilage cells for periostin in enchondroma, osteo- of bone and joint chondroma, or low/high-grade conventional chondro- Strong staining for periostin was seen in the osteoid sarcoma. The dense fibrous perichondrium covering matrix formed by osteoblastic cells in neoplastic and osteochondromas (which is continuous with the perios- non-neoplastic bone-forming lesions. Periostin stain- teum) stained strongly for periostin (Fig. 2a). At the base ing was noted in the osteoid matrix covering organized of growing osteochondromas, there was focal staining of reactive bone in fracture callus and myositis ossificans. the matrix and thin-walled vessels in areas of enchon- In osteoblastoma, newly formed osteoid stained strongly dral ossification and remodeling of newly formed bone. for periostin (Fig.  1a); staining for periostin was less In chondroblastoma, areas of chondroid matrix, some of pronounced in woven bone and was absent in lamel- which showed evidence of mineralisation, stained focally lar bone surrounding the lesion. In osteosarcoma, there for periostin (Fig.  2b). There was also focal staining of was strong staining for periostin in the osteoid matrix the matrix around chondroblasts. There was no stain - formed by malignant cells (Fig. 1b); staining for periostin ing for periostin in chondromyxoid fibroma. In clear cell was seen in all osteosarcomas but the extent of expres- chondrosarcoma, periostin staining was seen in the min- sion was variable with osteoid-rich tumours showing the eralized osteoid-like matrix covering woven bone and strongest and most diffuse staining (Fig.  1c). A similar cartilage formed by vacuolated tumor cells. pattern of staining for periostin was noted in lung nod- In aneurysmal bone cyst (ABC) and simple bone cyst, ules of metastatic osteosarcoma (Fig.  1d). In small cell the fibrous stroma and reactive bone within the cyst osteosarcoma, periostin was expressed in the matrix wall was positive for periostin (Fig.  3a). In giant cell between tumor cells (Fig.  1e). In chondroblastic and tumour of bone (GCTB), there was focal, occasionally telangiectatic osteosarcomas, cartilage and giant cell strong staining for periostin in the collagenous connec- components of the tumor were negative. In parosteal tive tissue matrix around mononuclear cells (Fig.  3b). osteosarcoma, periostin expression was noted focally in Giant cells in GCTB, chondroblastoma and ABC were Fig. 1 Immunohistochemical staining for periostin in osteoid/newly formed bone of: a osteoblastoma; b high-grade osteoblastic osteosarcoma; c osteoid-rich area of high-grade osteosarcoma; d small cell osteosarcoma; e osteosarcoma metastasis in lung; f fibrous dysplasia Brown et al. Clin Sarcoma Res (2018) 8:18 Page 4 of 8 Fig. 2 Immunohistochemical staining for periostin in: a benign Fig. 3 Immunohistochemical staining for periostin in: a aneurysmal osteochondroma showing staining of the perichondrium covering bone cyst showing matrix staining in fibrous tissue of the cyst the (unstained) cartilage; b chondroblastoma showing staining in wall; b giant cell tumour of bone showing matrix staining around areas containing mineralised chondroid (arrowed) mononuclear cells bone. Strong periostin staining of vessels was also seen negative for periostin. Variable focal staining for peri- within metastatic tumours (Fig. 4b). ostin was seen in cellular and collagenous connective tissue of other bone tumours, including non-ossifying Periostin expression in OA and RA fibroma and undifferentiated pleomorphic sarcoma. No Immunohistochemistry showed no staining for periostin specific staining for periostin was noted in Langerhans of synovial lining cells in OA or RA synovium. Strong cell histiocytosis, Ewing sarcoma, lymphoma, myeloma, staining for periostin was noted in RA in the superficial chordoma or adamantinoma. subintima where there was staining of the fibrous tissue Staining for periostin was noted in non-neoplastic matrix and the smooth muscle wall of small blood ves- bone at the edge of growing benign and malignant pri- sels in areas of increased vascularity (Fig. 5a); in contrast, mary bone tumours (Fig.  4a); this was in areas of fatty non-inflammatory OA synovium showed no subintimal marrow in which there was fibrosis, increased vascular - periostin staining; (Fig.  5b). Periostin was also expressed ity and reactive bone formation with prominent stain- in the matrix around large vessels in the deep subintima ing often noted in the smooth muscle wall of small and capsule of RA joints. ELISA studies showed that the blood vessels with lining endothelial cells unstained. average human periostin concentration in synovial fluid Infiltrating secondary carcinomas and melanomas that was 107.4  ng/ml and 67.1  ng/ml in RA patients and OA had metastasised to bone showed a similar pattern of patients respectively (Fig.  6). This was not of statistical staining for periostin in surrounding non-neoplastic significance (p = 0.29), but higher periostin levels were more frequently seen in RA than OA synovial fluid. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 5 of 8 Fig. 4 Immunohistochemical staining for periostin in: a osteosarcoma showing staining of vessels and matrix in fatty marrow in non-neoplastic bone at the tumour margin (arrowed); b metastatic melanoma showing prominent staining of vessels within the tumour Discussion In this study, we have characterised periostin expression in neoplastic and non-neoplastic lesions of bone and joint. In keeping with its role in bone matrix formation, periostin was found to be strongly expressed in osteoid/ bone-forming lesions; it was also noted in the mineral- ised chondroid/osteoid matrix of chondroblastomas and clear cell chondrosarcomas and in the connective tissue matrix of other primary bone tumours. Periostin expres- sion was also prominent in areas of reactive host bone around infiltrating primary and secondary bone tumours, suggesting a role for this matricellular protein in tumour progression. Periostin is a 90-kDa secreted protein which binds to type I collagen and other ECM proteins including fibronectin, Notch1, tenascin-C and BMP-1 [3–6, 18–20]; periostin acts to increase osteoblast proliferation, dif- ferentiation, adhesion and survival, and plays a key role in bone matrix formation. Periostin plays a role in bone remodelling by regulating collagen cross-linking and fibrillogenesis. In periostin-null mice, collagen fibrillo - genesis is disrupted in the periosteum and mechanical loading results in a disorganised matrix formation. In addition, periostin expression is associated with reduced sclerostin and preservation of bone mass. Periostin increases ECM production by fibroblasts/myofibroblasts and promotes mesenchymal stem cell differentiation into osteoblasts, resulting in the formation of bone matrix. Fig. 5 Immunohistochemical staining for periostin in: a RA synovium Periostin is known to function as a signalling molecule showing prominent staining of vessels in the subintima; b OA through integrin receptors and WNT-β-catenin path- synovium ways whereby it stimulates osteoblast function and bone formation. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 6 of 8 with those of Lai and Chen [22], who identified periostin in chondrosarcoma and enchondroma using a commer- cial mouse monoclonal antibody TA804575 (OriGene Technologies, Inc., Rockville, MD, USA); in our study we employed a rabbit polyclonal antibody that had been characterised in previous investigations [13, 17]. In both chondroblastoma and clear cell chondrosarcoma, strong expression of periostin was noted in areas of chondroid matrix formation. In chondroblastoma, the chondroid matrix has been described as “chondrosteoid” by some 0 observers [23]; it has been shown that this matrix con- RA OA tains dentine-matrix protein-1 and sclerostin, proteins Fig. 6 Amount of periostin in synovial fluid samples from RA and OA found in newly formed osteoid [24, 25]. Clear cell chon- patients (n = 9), quantified using ELISA drosarcoma, which is considered by some observers to be a malignant form of chondroblastoma [23], also showed expression of periostin in areas of woven bone formed Periostin was originally called osteoblast specific fac - within the clear cell cartilaginous stroma. tor-2 and in this study we have shown that periostin is We consistently noted increased expression of peri- highly expressed in reparative lesions associated with ostin in non-lesional bone at the edge of growing benign osteoid/woven bone formation, such as fracture callus and malignant bone tumours. It has been shown that per- and myositis ossificans as well as in benign and malignant iostin plays a role in the progression of inflammatory and bone-forming tumours. Expression of periostin in osteo- neoplastic lesions [6, 11, 12, 23]. Periostin is known to sarcoma has previously been reported with high expres- be expressed by fibroblasts in RA, carcinomas and other sion being correlated with tumour angiogenesis and poor malignant tumours [26–32]. Periostin is known to stimu- prognosis [14, 15]. We noted periostin expression in both late cell/matrix adhesion and migration of the endothelial low-grade parosteal osteosarcomas and high-grade con- cells through interaction with αVβ3 [33]. Endothelial cells ventional osteosarcomas as well as in lung metastases strongly express αVβ3 when stimulated by growth factors of osteosarcoma with the extent of periostin expression produced in inflammation, wound healing and tumours. appearing to be more related to formation of an osteoid We noted that periostin was frequently expressed in the matrix than histological parameters of tumour grade. smooth muscle wall of small blood vessels within non- Strong periostin expression was consistently noted in lesional bone around growing tumours, both benign and fibrous dysplasia and osteofibrous dysplasia, fibro-osse - malignant. Interactions between periostin and vascular ous bone tumours in which there is formation of woven endothelial growth factor (VEGF) and its receptors are bone with intramembranous ossification similar to that thought to play a key role in physiological and pathologi- which occurs beneath the periosteum. Periostin was cal angiogenesis [6, 12, 29, 34–36]. Periostin is strongly also seen in cellular fibrous tissue and areas of reactive expressed by vascular smooth muscle cells, particularly osteoid/bone formation in other bone lesions, including those which are activated and migrating from the media simple bone cyst, ABC, fracture callus and myositis ossi- to the intima or proliferating and synthesising matrix ficans. It was also noted in the connective tissue matrix proteins. It has been shown that in breast carcinoma, around mononuclear cells in giant cell tumour of bone; squamous cell carcinoma and other tumours, blood ves- these cells are known to exhibit several osteoblast mark- sel density in periostin-positive tumours is higher than ers including alkaline phosphatase, RUNX2, osterix and in periostin-negative tumours with increased tumour RANKL [21]. Focal but less prominent staining for peri- invasion and metastasis being reported in these periostin ostin was also noted in cellular and collagenous fibrous over-expressing tumours [28, 37–40]. We noted promi- tissue of other primary bone tumours including non-ossi- nent staining of the smooth muscle wall of small blood fying fibroma and undifferentiated pleomorphic sarcoma. vessels in malignant tumours that had metastasised to Periostin was strongly expressed in the perichondrium bone. covering osteochondromas and in areas of endochondral There were similarities in the pattern of periostin ossification at the base of growing osteochondromas but expression in inflamed RA synovium and growing bone there was no staining in cells or matrix of the cartilage tumours. Periostin is known to be involved in the migra- cap. Periostin expression was absent in other cartilage tion of synovial fibroblasts associated with RA pannus tumours including enchondroma and low/high-grade formation and joint destruction [4, 10]. We noted strong conventional chondrosarcoma. Our findings contrast expression of periostin in the subintimal connective ng/ml Brown et al. Clin Sarcoma Res (2018) 8:18 Page 7 of 8 Availability of data and materials tissue matrix and smooth muscle wall of small blood ves- Not applicable. sels in RA synovium, indicating that periostin-associated angiogenesis may play a role in RA disease progression. Consent to publish Not applicable. We also noted higher levels of periostin in RA compared with OA synovial fluid and little staining for periostin in Ethics approval and consent to participate OA synovium. Increased levels of periostin have been This study was approved by the Central Oxford Research Ethics Committee (C01.070 and C01.071). Informed consent was obtained from the use of tissue associated with tumour angiogenesis, metastatic poten- in this study. tial and poor prognosis in osteosarcoma patients [14, 15]. It has been shown that small interfering RNA against Funding This study was supported by the Sasakawa Foundation and the European periostin significantly reduces the migration of fibroblast- Union through funding of the EuroBoNet and EuroSarc consortiums. The like cells in RA [10]. Analogously, inhibition of periostin funders played no role in the collection of data, interpretation of results or gene expression suppresses the proliferation and inva- writing of the manuscript. sion of U2OS osteosarcoma cells [41] Our immunohisto- chemical finding of increased expression of periostin at Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- the edge of growing bone tumours is in keeping with a lished maps and institutional affiliations. role for periostin in tumour growth and, taken with the results of previous studies, suggests that periostin could Received: 6 July 2018 Accepted: 4 August 2018 represent a potential therapeutic target to control the growth of osteosarcoma and other bone tumours. References 1. Takeshita S, Kikuno R, Tezuka K, Amann E. 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Periostin expression in neoplastic and non-neoplastic diseases of bone and joint

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Springer Journals
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Copyright © 2018 by The Author(s)
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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10.1186/s13569-018-0105-y
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Abstract

Background: Periostin is a matricellular protein that is expressed in bone and joint tissues. To determine the expres- sion of periostin in primary bone tumours and to assess whether it plays a role in tumour progression, we carried out immunohistochemistry and ELISA for periostin in a range of neoplastic and non-neoplastic bone and joint lesions. Methods: 140 formalin-fixed paraffin-embedded sections of bone tumours and tumour-like lesions were stained by an indirect immunoperoxidase technique with a polyclonal anti-periostin antibody. Periostin expression was also assessed in rheumatoid arthritis (RA) and non-inflammatory osteoarthritis (OA) synovium and synovial fluid immuno - histochemistry and ELISA respectively. Results: Periostin was most strongly expressed in osteoid/woven bone of neoplastic and non-neoplastic bone- forming lesions, including osteoblastoma, osteosarcoma, fibrous dysplasia, osteofibrous dysplasia, fracture callus and myositis ossificans, and mineralised chondroid matrix/woven bone in chondroblastoma and clear cell chondrosar - coma. Reactive host bone at the edge of growing tumours, particularly in areas of increased vascularity and fibrosis, also stained strongly for periostin. Vascular elements in RA synovium strongly expressed periostin, and synovial fluid levels of periostin were higher in RA than OA. Conclusions: In keeping with its known role in modulating the synthesis of collagen and other extracellular matrix proteins in bone, strong periostin expression was noted in benign and malignant lesions forming an osteoid or oste- oid-like matrix. Periostin was also noted in other bone tumours and was found in areas of reactive bone and increased vascularity at the edge of growing tumours, consistent with its involvement in tissue remodelling and angiogenesis associated with tumour progression. Keywords: Periostin expression, Bone tumours, Tumour progression Background matrix (ECM) proteins [3–6]. Periostin has a multi- Periostin, a secreted extracellular matrix protein that domain structure in which particular domains bind to belongs to the fasciclin family, was originally character- many proteins and enzymes that promote ECM protein ised in osteoblasts and first termed osteoblast-specific crosslinking. Periostin is involved in the formation and factor 2 [1, 2]. Periostin is a matricellular protein that maintenance of normal bone and teeth tissues and is does not have a specific structural role but rather inter - highly expressed in tissue components that are subject to mechanical stress, such as the periosteum and the acts with cell surface receptors, proteases and other periodontal ligament. It has also been observed in other molecules that modulate cell adhesion/migration and organs and tissues including heart, breast, lung, thyroid, the fibrillogenesis of collagen and other extracellular skin, placenta and ovary [3–6]. Periostin is expressed at sites of injury/repair and *Correspondence: nick.athanasou@ndorms.ox.ac.uk inflammation [ 3, 6, 7]. It has been identified in rheu 1 - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Sciences, Nuffield Orthopaedic Centre, matoid arthritis (RA) and osteoarthritis (OA) joints University of Oxford, Oxford OX3 7HE, UK [8, 9] with a recent study identifying periostin as a key Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 2 of 8 regulator in RA synoviocyte migration/invasion asso- Table 1 Bone tumours/tumour-like lesions analysed in this study ciated with pannus formation [10]. Periostin is also expressed in a number of cancers where it is thought, by Tissue type Number various mechanisms, to play a role in tumour progression analysed [3, 6, 11, 12]. Periostin has been identified in a few bone Osteoma 2 tumours, including fibrous dysplasia and osteosarcoma Osteoid osteoma 4 [13–15], but its expression in other bone neoplasms has Osteoblastoma 6 not been fully investigated. Osteosarcoma, conventional 20 In this study we investigated immunophenotypic Osteosarcoma, telangiectatic 2 expression of periostin in a wide range of primary Osteosarcoma, small cell 2 tumours and tumour-like lesions of bone as well as in Osteosarcoma, parosteal 2 bone secondaries and metastatic osteosarcomas. Our Fibrous dysplasia 10 aims were two-fold: first, to determine whether periostin Osteofibrous dysplasia 2 expression is increased in specific bone tumour types; Fracture 2 and second, to examine whether periostin plays a role in Myositis ossificans 2 tumour progression. Enchondroma 3 Chondroblastoma 9 Methods Chondromyxoid fibroma 3 Neoplastic and non‑neoplastic tissue samples analysed Chondrosarcoma, conventional 20 Tissue samples from 140 biopsies or surgical resections Chondrosarcoma, clear cell 5 of bone tumours and tumour-like lesions, were retrieved Giant cell tumour of bone 8 from the files of the Nuffield Orthopaedic Centre, His - Aneurysmal bone cyst 4 topathology Department, Oxford (Table  1). Criteria for Solitary bone cyst 2 the histological diagnosis of bone and joint lesions inves- Non-ossifying fibroma 3 tigated in this study were those of the 2013 WHO Clas- Undifferentiated pleomorphic sarcoma 3 sification of Tumours of Soft Tissue and Bone [16]. The Ewing sarcoma 6 tissues were fixed in 10% buffered formalin and, where Adamantinoma of long bone 1 necessary, decalcified in 5% nitric acid or EDTA. In addi - Chordoma 2 tion, formalin-fixed paraffin-embedded sections of syno - Plasma cell myeloma 2 vial tissue derived from patients with RA (n = 21) and Lymphoma 2 OA (n = 19) were examined. Samples of normal bone and Langerhans cell histiocytoma 2 joint tissues from amputation specimens of individuals Metastatic breast carcinoma 3 with no history or evidence of joint disease or neoplasia Metastatic melanoma 1 were used as controls. Synovial fluid (SF) was also aspi - rated from the knee joint of nine patients with OA and nine patients with RA. Ethics approval was obtained from the National Research Ethical Committee, and patient (enzyme-linked immunosorbent assay). The periostin consent was acquired prior to the collection of samples. concentration was assessed using a Human periostin/ OSF-2 ELISA kit (Adiopo bioscience, Santa Clara, CA, Immunohistochemistry for periostin USA). Statistical evaluation was performed using the Immunohistochemical staining for periostin was carried Mann–Whitney U test with p values less than 0.05 con- out by an indirect immunoperoxidase technique (without sidered as statistically significant. any antigen retrieval procedure) using a polyclonal rab- bit antiserum against human periostin raised by using Results peptide DNLDSDIRRGLESNVN (representing aminoac- Periostin expression in normal bone and joint tissues ids 143–158 of human periostin) as an immunogen [13, In normal bone there was strong expression of peri- 17]. As in previous studies [17], the antibody dilution was ostin in collagenous fibrous tissue of the periosteum. At 1:250 and sections of normal skin were employed as a points of tendon or ligament insertion into bone, strong positive control. periostin staining was also seen within collagenous tis- sue. There was no staining for periostin in normal lamel - lar cortical and cancellous bone, and osteocytes, bone Periostin expression in OA and RA synovial fluid lining cells, osteoblasts and osteoclasts did not express A quantitative measure of the level of periostin in knee periostin. Fatty and hematopoietic marrow was generally joint RA and OA synovial fluid was determined by ELISA Brown et al. Clin Sarcoma Res (2018) 8:18 Page 3 of 8 negative for periostin but, in some specimens, staining the matrix in areas of tumor cell proliferation. There was for periostin was noted in small sinusoidal vascular chan- strong staining for periostin in fibrous dysplasia and oste - nels within the marrow. In normal joints, the synovium ofibrous dysplasia, predominantly in the cellular fibrous and hyaline articular cartilage did not stain for periostin. stroma between bone trabeculae (Fig. 1f ). There was no specific staining of the chondroid matrix Periostin expression in tumours and tumour‑like lesions or cartilage cells for periostin in enchondroma, osteo- of bone and joint chondroma, or low/high-grade conventional chondro- Strong staining for periostin was seen in the osteoid sarcoma. The dense fibrous perichondrium covering matrix formed by osteoblastic cells in neoplastic and osteochondromas (which is continuous with the perios- non-neoplastic bone-forming lesions. Periostin stain- teum) stained strongly for periostin (Fig. 2a). At the base ing was noted in the osteoid matrix covering organized of growing osteochondromas, there was focal staining of reactive bone in fracture callus and myositis ossificans. the matrix and thin-walled vessels in areas of enchon- In osteoblastoma, newly formed osteoid stained strongly dral ossification and remodeling of newly formed bone. for periostin (Fig.  1a); staining for periostin was less In chondroblastoma, areas of chondroid matrix, some of pronounced in woven bone and was absent in lamel- which showed evidence of mineralisation, stained focally lar bone surrounding the lesion. In osteosarcoma, there for periostin (Fig.  2b). There was also focal staining of was strong staining for periostin in the osteoid matrix the matrix around chondroblasts. There was no stain - formed by malignant cells (Fig. 1b); staining for periostin ing for periostin in chondromyxoid fibroma. In clear cell was seen in all osteosarcomas but the extent of expres- chondrosarcoma, periostin staining was seen in the min- sion was variable with osteoid-rich tumours showing the eralized osteoid-like matrix covering woven bone and strongest and most diffuse staining (Fig.  1c). A similar cartilage formed by vacuolated tumor cells. pattern of staining for periostin was noted in lung nod- In aneurysmal bone cyst (ABC) and simple bone cyst, ules of metastatic osteosarcoma (Fig.  1d). In small cell the fibrous stroma and reactive bone within the cyst osteosarcoma, periostin was expressed in the matrix wall was positive for periostin (Fig.  3a). In giant cell between tumor cells (Fig.  1e). In chondroblastic and tumour of bone (GCTB), there was focal, occasionally telangiectatic osteosarcomas, cartilage and giant cell strong staining for periostin in the collagenous connec- components of the tumor were negative. In parosteal tive tissue matrix around mononuclear cells (Fig.  3b). osteosarcoma, periostin expression was noted focally in Giant cells in GCTB, chondroblastoma and ABC were Fig. 1 Immunohistochemical staining for periostin in osteoid/newly formed bone of: a osteoblastoma; b high-grade osteoblastic osteosarcoma; c osteoid-rich area of high-grade osteosarcoma; d small cell osteosarcoma; e osteosarcoma metastasis in lung; f fibrous dysplasia Brown et al. Clin Sarcoma Res (2018) 8:18 Page 4 of 8 Fig. 2 Immunohistochemical staining for periostin in: a benign Fig. 3 Immunohistochemical staining for periostin in: a aneurysmal osteochondroma showing staining of the perichondrium covering bone cyst showing matrix staining in fibrous tissue of the cyst the (unstained) cartilage; b chondroblastoma showing staining in wall; b giant cell tumour of bone showing matrix staining around areas containing mineralised chondroid (arrowed) mononuclear cells bone. Strong periostin staining of vessels was also seen negative for periostin. Variable focal staining for peri- within metastatic tumours (Fig. 4b). ostin was seen in cellular and collagenous connective tissue of other bone tumours, including non-ossifying Periostin expression in OA and RA fibroma and undifferentiated pleomorphic sarcoma. No Immunohistochemistry showed no staining for periostin specific staining for periostin was noted in Langerhans of synovial lining cells in OA or RA synovium. Strong cell histiocytosis, Ewing sarcoma, lymphoma, myeloma, staining for periostin was noted in RA in the superficial chordoma or adamantinoma. subintima where there was staining of the fibrous tissue Staining for periostin was noted in non-neoplastic matrix and the smooth muscle wall of small blood ves- bone at the edge of growing benign and malignant pri- sels in areas of increased vascularity (Fig. 5a); in contrast, mary bone tumours (Fig.  4a); this was in areas of fatty non-inflammatory OA synovium showed no subintimal marrow in which there was fibrosis, increased vascular - periostin staining; (Fig.  5b). Periostin was also expressed ity and reactive bone formation with prominent stain- in the matrix around large vessels in the deep subintima ing often noted in the smooth muscle wall of small and capsule of RA joints. ELISA studies showed that the blood vessels with lining endothelial cells unstained. average human periostin concentration in synovial fluid Infiltrating secondary carcinomas and melanomas that was 107.4  ng/ml and 67.1  ng/ml in RA patients and OA had metastasised to bone showed a similar pattern of patients respectively (Fig.  6). This was not of statistical staining for periostin in surrounding non-neoplastic significance (p = 0.29), but higher periostin levels were more frequently seen in RA than OA synovial fluid. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 5 of 8 Fig. 4 Immunohistochemical staining for periostin in: a osteosarcoma showing staining of vessels and matrix in fatty marrow in non-neoplastic bone at the tumour margin (arrowed); b metastatic melanoma showing prominent staining of vessels within the tumour Discussion In this study, we have characterised periostin expression in neoplastic and non-neoplastic lesions of bone and joint. In keeping with its role in bone matrix formation, periostin was found to be strongly expressed in osteoid/ bone-forming lesions; it was also noted in the mineral- ised chondroid/osteoid matrix of chondroblastomas and clear cell chondrosarcomas and in the connective tissue matrix of other primary bone tumours. Periostin expres- sion was also prominent in areas of reactive host bone around infiltrating primary and secondary bone tumours, suggesting a role for this matricellular protein in tumour progression. Periostin is a 90-kDa secreted protein which binds to type I collagen and other ECM proteins including fibronectin, Notch1, tenascin-C and BMP-1 [3–6, 18–20]; periostin acts to increase osteoblast proliferation, dif- ferentiation, adhesion and survival, and plays a key role in bone matrix formation. Periostin plays a role in bone remodelling by regulating collagen cross-linking and fibrillogenesis. In periostin-null mice, collagen fibrillo - genesis is disrupted in the periosteum and mechanical loading results in a disorganised matrix formation. In addition, periostin expression is associated with reduced sclerostin and preservation of bone mass. Periostin increases ECM production by fibroblasts/myofibroblasts and promotes mesenchymal stem cell differentiation into osteoblasts, resulting in the formation of bone matrix. Fig. 5 Immunohistochemical staining for periostin in: a RA synovium Periostin is known to function as a signalling molecule showing prominent staining of vessels in the subintima; b OA through integrin receptors and WNT-β-catenin path- synovium ways whereby it stimulates osteoblast function and bone formation. Brown et al. Clin Sarcoma Res (2018) 8:18 Page 6 of 8 with those of Lai and Chen [22], who identified periostin in chondrosarcoma and enchondroma using a commer- cial mouse monoclonal antibody TA804575 (OriGene Technologies, Inc., Rockville, MD, USA); in our study we employed a rabbit polyclonal antibody that had been characterised in previous investigations [13, 17]. In both chondroblastoma and clear cell chondrosarcoma, strong expression of periostin was noted in areas of chondroid matrix formation. In chondroblastoma, the chondroid matrix has been described as “chondrosteoid” by some 0 observers [23]; it has been shown that this matrix con- RA OA tains dentine-matrix protein-1 and sclerostin, proteins Fig. 6 Amount of periostin in synovial fluid samples from RA and OA found in newly formed osteoid [24, 25]. Clear cell chon- patients (n = 9), quantified using ELISA drosarcoma, which is considered by some observers to be a malignant form of chondroblastoma [23], also showed expression of periostin in areas of woven bone formed Periostin was originally called osteoblast specific fac - within the clear cell cartilaginous stroma. tor-2 and in this study we have shown that periostin is We consistently noted increased expression of peri- highly expressed in reparative lesions associated with ostin in non-lesional bone at the edge of growing benign osteoid/woven bone formation, such as fracture callus and malignant bone tumours. It has been shown that per- and myositis ossificans as well as in benign and malignant iostin plays a role in the progression of inflammatory and bone-forming tumours. Expression of periostin in osteo- neoplastic lesions [6, 11, 12, 23]. Periostin is known to sarcoma has previously been reported with high expres- be expressed by fibroblasts in RA, carcinomas and other sion being correlated with tumour angiogenesis and poor malignant tumours [26–32]. Periostin is known to stimu- prognosis [14, 15]. We noted periostin expression in both late cell/matrix adhesion and migration of the endothelial low-grade parosteal osteosarcomas and high-grade con- cells through interaction with αVβ3 [33]. Endothelial cells ventional osteosarcomas as well as in lung metastases strongly express αVβ3 when stimulated by growth factors of osteosarcoma with the extent of periostin expression produced in inflammation, wound healing and tumours. appearing to be more related to formation of an osteoid We noted that periostin was frequently expressed in the matrix than histological parameters of tumour grade. smooth muscle wall of small blood vessels within non- Strong periostin expression was consistently noted in lesional bone around growing tumours, both benign and fibrous dysplasia and osteofibrous dysplasia, fibro-osse - malignant. Interactions between periostin and vascular ous bone tumours in which there is formation of woven endothelial growth factor (VEGF) and its receptors are bone with intramembranous ossification similar to that thought to play a key role in physiological and pathologi- which occurs beneath the periosteum. Periostin was cal angiogenesis [6, 12, 29, 34–36]. Periostin is strongly also seen in cellular fibrous tissue and areas of reactive expressed by vascular smooth muscle cells, particularly osteoid/bone formation in other bone lesions, including those which are activated and migrating from the media simple bone cyst, ABC, fracture callus and myositis ossi- to the intima or proliferating and synthesising matrix ficans. It was also noted in the connective tissue matrix proteins. It has been shown that in breast carcinoma, around mononuclear cells in giant cell tumour of bone; squamous cell carcinoma and other tumours, blood ves- these cells are known to exhibit several osteoblast mark- sel density in periostin-positive tumours is higher than ers including alkaline phosphatase, RUNX2, osterix and in periostin-negative tumours with increased tumour RANKL [21]. Focal but less prominent staining for peri- invasion and metastasis being reported in these periostin ostin was also noted in cellular and collagenous fibrous over-expressing tumours [28, 37–40]. We noted promi- tissue of other primary bone tumours including non-ossi- nent staining of the smooth muscle wall of small blood fying fibroma and undifferentiated pleomorphic sarcoma. vessels in malignant tumours that had metastasised to Periostin was strongly expressed in the perichondrium bone. covering osteochondromas and in areas of endochondral There were similarities in the pattern of periostin ossification at the base of growing osteochondromas but expression in inflamed RA synovium and growing bone there was no staining in cells or matrix of the cartilage tumours. Periostin is known to be involved in the migra- cap. Periostin expression was absent in other cartilage tion of synovial fibroblasts associated with RA pannus tumours including enchondroma and low/high-grade formation and joint destruction [4, 10]. We noted strong conventional chondrosarcoma. Our findings contrast expression of periostin in the subintimal connective ng/ml Brown et al. Clin Sarcoma Res (2018) 8:18 Page 7 of 8 Availability of data and materials tissue matrix and smooth muscle wall of small blood ves- Not applicable. sels in RA synovium, indicating that periostin-associated angiogenesis may play a role in RA disease progression. Consent to publish Not applicable. We also noted higher levels of periostin in RA compared with OA synovial fluid and little staining for periostin in Ethics approval and consent to participate OA synovium. Increased levels of periostin have been This study was approved by the Central Oxford Research Ethics Committee (C01.070 and C01.071). Informed consent was obtained from the use of tissue associated with tumour angiogenesis, metastatic poten- in this study. tial and poor prognosis in osteosarcoma patients [14, 15]. It has been shown that small interfering RNA against Funding This study was supported by the Sasakawa Foundation and the European periostin significantly reduces the migration of fibroblast- Union through funding of the EuroBoNet and EuroSarc consortiums. The like cells in RA [10]. Analogously, inhibition of periostin funders played no role in the collection of data, interpretation of results or gene expression suppresses the proliferation and inva- writing of the manuscript. sion of U2OS osteosarcoma cells [41] Our immunohisto- chemical finding of increased expression of periostin at Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- the edge of growing bone tumours is in keeping with a lished maps and institutional affiliations. role for periostin in tumour growth and, taken with the results of previous studies, suggests that periostin could Received: 6 July 2018 Accepted: 4 August 2018 represent a potential therapeutic target to control the growth of osteosarcoma and other bone tumours. References 1. Takeshita S, Kikuno R, Tezuka K, Amann E. 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Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Sep 5, 2018

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