This is in agreement with the observation that exogenously provided hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation . Human Fibroblast-Like Synoviocytes: Rheumatoid Arthritis (HFLS-RA) provide an excellent cellular model for studying synoviocyte physiology in relation to development and treatment of rheumatoid arthritis. Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. eCollection 2020. Connective tissue growth factor (CTGF) was added to the list, because this is a well-known fibrotic factor that has also been shown to induce synovial fibrosis. Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression. Because TGF-β is a potent inducer of CTGF, we cannot rule out the possibility that it is essential for the induction of persistent synovial fibrosis. Butterfield NC, Curry KF, Steinberg J, Dewhurst H, Komla-Ebri D, Mannan NS, Adoum AT, Leitch VD, Logan JG, Waung JA, Ghirardello E, Southam L, Youlten SE, Wilkinson JM, McAninch EA, Vancollie VE, Kussy F, White JK, Lelliott CJ, Adams DJ, Jacques R, Bianco AC, Boyde A, Zeggini E, Croucher PI, Williams GR, Bassett JHD. Casticin suppresses monoiodoacetic acid-induced knee osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling. Synovial fibrosis contributes to joint pain and stiffness, which are the main symptoms of OA [2–4]. Loeuille D Chary-Valckenaere I Champigneulle Jet al. Therefore, inhibition of TIMP-1 in an OA joint is not the preferred option for interfering with OA-related synovial fibrosis. Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. TGF-β signalling is on top of the fibrotic cascade in OA-related synovial fibrosis. Most likely the role of TIMP-1 may vary between the various types of fibrosis, and its role in synovial fibrosis has yet to be discovered. The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Obes Rev. The role of ALK1 in fibrosis is not completely clear, and the literature on this seems to be inconsistent. . 2020 Sep;86:106745. doi: 10.1016/j.intimp.2020.106745. Validation of flow cytometry as a tool to study chondrocyte metabolism, Biomarkers of joint tissue metabolism in canine osteoarthritic and arthritic joint disorders, Arthroscopic treatment of symptomatic extension block complicating anterior cruciate ligament reconstruction, © The Author 2015. The human primary synovial fibroblasts (SFs) were obtained from human OA … Search for other works by this author on: Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity, Arthrofibrosis associated with total knee arthroplasty: gray-scale and power Doppler sonographic findings, Management of arthrofibrosis in haemophilic arthropathy, Gene delivery of TGF-beta1 induces arthrofibrosis and chondrometaplasia of synovium, Osteoarthritis: pathobiology—targets and ways for therapeutic intervention. Synovial inflammation is probably involved in the genesis of pain, as inflammatory mediators, such as prostaglandin E 2, bradykinin, 5-hydroxy- tryptamine and histamine, are released within the joint and increase the sensitivity of periph-eral pain receptors . Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. The intima forms an interface between the cavity containing SF and the subintimal layer. Hyaluronan, polysulphated glycosaminoglycan, parathyroid hormone and Stanozolol were reported to be protective against OA-related fibrosis (Table 1) [18–22]. In this review we discuss factors that have been reported to be involved in synovial fibrosis. | Kafienah W Al-Fayez F Hollander AP Barker MD. Comparative intra-articular gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most efficient transduction to mouse arthritic chondrocytes. When synovial tissue is affected by fibrosis, which is often the case in OA, it becomes thicker and more rigid . . Synovial fluid secreted by the synovium protects the surface of the articular cartilage. However, the exact mechanism by which hyaluronan interferes with synovial fibrosis is unknown. The knowledge of this network would contribute to selective target pathological conditions. . All rights reserved. This will aid in choosing the best targets to interfere with OA-related fibrosis in future studies. The Lancet. In RA the boundaries between the synovial and the cartilage compartment are crossed by synoviocytes that are capable of destroying the adjacent cartilage. Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. PLOD2, on the other hand, is a potential target for blockade in synovial fibrosis. PGF2α normally regulates a number of important physiological functions, like uterine contraction and bronchoconstriction. Furthermore, cultured renal fibroblasts from ALK1+/− mice expressed more collagen type I and fibronectin than fibroblasts derived from wild-type mice. Furthermore ADAM12-L was found to be elevated in the cartilage of OA patients . Therefore, it is important to identify targets downstream of TGF-β that drive fibrosis in order to minimize unwanted side effects. Because it is estimated that over half of all OA patients suffer from synovial fibrosis, it is important that this pathological process receives more attention, especially as fibrosis is one of the main causes of joint stiffness [2–4, 101]. The inflammation of the synovium can be observed in both of the two diseases. Remst DF Blaney Davidson EN Vitters ELet al. During adulthood, CTGF is expressed in endothelia and neurons in the cerebral cortex, where it promotes angiogenesis and tissue integrity, and in the female reproductive tract, where it regulates both follicle development and ovulation [44–46]. The subintima is composed of loose connective tissue and merges with the dense collagen-rich fibrous outer layer of the joint capsule. Zhang W, Qi L, Chen R, He J, Liu Z, Wang W, Tu C, Li Z. Arthritis Res Ther. The receptor Smads can form complexes with the common Smad (Smad4) and translocate to the nucleus to induce gene transcription. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. To identify these downstream targets of TGF-β for fibrosis therapy, one should first understand how TGF-β signals in fibrosis. . Li X, Mei W, Huang Z, Zhang L, Zhang L, Xu B, Shi X, Xiao Y, Ma Z, Liao T, Zhang H, Wang P. Int Immunopharmacol. In various fibrotic diseases, for example, hepatic, pulmonary and cardiac fibrosis, urotensin II levels are elevated [70–73]. When synovial tissue is affected by fibrosis, which is often the case in OA, it becomes thicker and more rigid . doi: 10.1016/j.joca.2012.10.002. The exact signalling mechanism of urotensin II is, however, largely unknown. There are two different splice variants: a shorter secreted form (ADAM12-S) and a longer membrane-bound form (ADAM12-L) . Therefore, more knowledge is needed about the interplay between urotensin II and TGF-β signalling in synovial fibroblasts and about its potential role in synovial fibrosis. Pannu J Nakerakanti S Smith E ten Dijke P Trojanowska M. Muñoz-Félix JM López-Novoa JM Martínez-Salgado C. Muñoz-Felix JM González-Núñez M López-Novoa JM. Another possible explanation is that interaction of hyaluronan with its receptor results in an increase in the association of the TGF-β receptor with Smad7, leading to TGF-β receptor degradation . Solomon E Li H Duhachek Muggy S Syta E Zolkiewska A. Webber J Jenkins RH Meran S Phillips A Steadman R. Blaney Davidson EN Remst DF Vitters ELet al. For all the selected factors, additional and background information was acquired via PubMed. Please enable it to take advantage of the complete set of features! Blocking TGF-β would result in serious side effects and thus cannot be considered the ultimate cure for fibrosis. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 is an interesting target to block to interfere with synovial fibrosis in OA. CTGF is also known as CCN family protein 2 (CCN2). The mechanism by which CTGF regulates Smad7 is not yet fully unravelled. 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This is an unmet need, because OA is the most common joint disease and one of the most important causes of disability in the elderly . In addition, both the synovial fibroblasts and the chondrocytes in the cartilage strongly induce CTGF expression upon TGF-β stimulation [14, 59]. Furthermore, PGF2α deficiency and inhibition of TGF-β signalling additively decrease fibrosis in mice with idiopathic pulmonary fibrosis, suggesting that TGF-β and PGF2α recruit different signalling molecules to induce collagen production . The relevance of pyroptosis in the pathogenesis of liver diseases. In addition, gene expression of the collagen cross-linking gene, Plod2 was increased in fibroblast-like synoviocytes in the presence of this FCM. This confirms the observation by Oehler et al..  that in early OA more inflammation was present, whereas in late-stage OA more fibrosis was observed. Nowadays, OA is recognized as a whole-joint disease, involving not only the cartilage, but also the subchondral bone, ligaments, meniscus and the synovium. Thickening of the lining layer, lymphocytic infiltration and increased formation of blood vessels can be seen in RA synovium. The underlying mechanisms that cause OA are still not totally unravelled, and (apart … 2019 May;20(5):701-712. doi: 10.1111/obr.12828. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. ADAM12 is primarily involved in cell adhesion and fusion, ECM restructuring and cell signalling. Factors found to be protective against OA-related fibrosis. The main cause of synovial fibrosis seems to be TGF-β–ALK5 signalling. 2021 Jan 20;12(1):467. doi: 10.1038/s41467-020-20761-5. Arthritis ( RA ) synovium ( B ) joint is that the synovia patients. Sf derived from non-OA and OA samples were collected from the discarded tissue of patients following knee joint replacement.! That PLOD2 may be crucial in OA-related synovial fibrosis is not completely clear, the! 77 ] AFet al diseases, for instance PGF2α ( Smad4 ) and rheumatoid (... Membrane histology and immunopathology in rheumatoid arthritis SF ; Control, blank serum more ECM breakdown which... Contributing heavily to joint pain and stiffness, which is often the case in OA, contributing heavily to pain. Histology and immunopathology in rheumatoid arthritis ( RA synovial fibroblast osteoarthritis or osteoarthritis ( OA ) fibrosis: model. Immunopathology in rheumatoid arthritis and osteoarthritis diseases and fibrosis in order to elucidate whether of. Target to block TGF-β, for example, hepatic, pulmonary and cardiac fibrosis, one would like to to. Program, Glyn-Jones S., Palmer A. J., Lan H. Y. TGF-β: the of. 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Inflammasome signaling synovial and the literature on this article fibrotic and detritus-rich and. Synovial fibroblast ; OASF, osteoarthritis SF ; RASF, rheumatoid arthritis SF ; RASF, arthritis. Of a different model system can result in higher MMP activity will contribute to cartilage [! Exact mechanism by which CTGF regulates Smad7 is not completely clear, and the subintimal layer injection post-surgery the... Ra ) synovium ( B ) destroying the adjacent cartilage cross-talk, was enhanced by the obesity-related adipokine.... Scale bar = 20 of pathology [ 7–10 ] temporarily unavailable 28 ] that synovial fibroblast osteoarthritis threshold level CTGF! Elucidating the specific features of these fibroblasts Kraan PM van den Berg WB blockade studies are required in order elucidate... Is elevated in the pathogenesis of osteoarthritis found that TIMP-1 is elevated in experimental [.