It is suggested by Leask and Abraham [51] that CTGF mediates its effects through integrin- and heparin sulphate proteoglycan–dependent mechanisms, and that the ability of CTGF to bind cell surface heparin sulphate proteoglycans (which are present at high levels in the joint) is essential for CTGF activity. . Because the specific roles of either Smad2 or Smad3 can be tissue dependent, the individual functions of Smad2 and Smad3 in the synovium have yet to be determined. Circular RNAs in osteoarthritis: indispensable regulators and novel strategies in clinical implications. Where others have demonstrated that only the combination of TGF-β and CTGF leads to persistent fibrosis, we have previously published that overexpression of TGF-β alone causes persistent synovial fibrosis, whereas CTGF alone in the murine knee joint causes only transient synovial fibrosis [27, 28, 57, 58]. When synovial tissue is affected by fibrosis, which is often the case in OA, it becomes thicker and more rigid [1]. Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Fibroblast-like synoviocytes (FLS) represent a specialised cell type located inside joints in the synovium.These cells play a crucial role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis.. Fibroblast-like synoviocytes in normal tissues. 2019 Apr 15;223:69-73. doi: 10.1016/j.lfs.2019.02.060. ADAM12 is primarily involved in cell adhesion and fusion, ECM restructuring and cell signalling. The synovial membrane in osteoarthritis: a histological study including the characterisation of the cellular infiltrate present in inflammatory osteoarthritis using monoclonal antibodies, The ADAM12 is upregulated in synovitis and postinflammatory fibrosis of the synovial membrane in patients with early radiographic osteoarthritis, Gene expression analysis of murine and human osteoarthritis synovium reveals elevation of transforming growth factor β-responsive genes in osteoarthritis-related fibrosis, Stimulation of fibrotic processes by the infrapatellar fat pad in cultured synoviocytes from patients with osteoarthritis: a possible role for prostaglandin f2alpha, TGF-ss induces Lysyl hydroxylase 2b in human synovial osteoarthritic fibroblasts through ALK5 signaling, Urotensin II (U-II), a novel cyclic peptide, possibly associated with the pathophysiology of osteoarthritis, Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis, Advance Access published 20 March 2014, doi: 10.1136/annrheumdis-2013-204599, Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis, Effects of intraarticular treatment with stanozolol on synovial membrane and cartilage in an ovine model of osteoarthritis, Effects of PTH [1-34] on synoviopathy in an experimental model of osteoarthritis preceded by osteoporosis, Evaluation of polysulfated glycosaminoglycan or sodium hyaluronan administered intra-articularly for treatment of horses with experimentally induced osteoarthritis, Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism, Significant synovial pathology in a meniscectomy model of osteoarthritis: modification by intra-articular hyaluronan therapy, TGF-beta signaling and the fibrotic response, Organ fibrosis inhibited by blocking transforming growth factor-beta signaling via peroxisome proliferator-activated receptor gamma agonists, Pathogenesis of fibrosis: role of TGF-beta and CTGF, Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression, Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease, Extracellular control of TGFbeta signalling in vascular development and disease, ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney, Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways, Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts, Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy. 2016;12(6):325–338. Kafienah W Al-Fayez F Hollander AP Barker MD. Nature Reviews Nephrology. Epub 2018 Jan 30. (a) The silencing…, Inhibition of FLS pyroptosis may alleviate fibrosis. Kerna et al.. [11] reported an enhanced level of inflammation, lining layer thickness, number of CD4+ T cells and macrophage infiltration in patients with very early OA compared with late-stage OA. This is in agreement with the observation that exogenously provided hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation [87]. This may be worth investigating, because besides the potential antifibrotic effects, inhibition of ALK1 is expected to reduce MMP13 expression in chondrocytes and therefore MMP-mediated cartilage damage—a potential win–win situation [90, 91]. In RA the boundaries between the synovial and the cartilage compartment are crossed by synoviocytes that are capable of destroying the adjacent cartilage. Ideally, to prevent fibrosis, one would like to block TGF-β, the top of the fibrotic cascade. 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. The fibroblast activation protein alpha+ (FAPα+) thymus cell antigen 1+(THY1+) FLS, located in the synovial sub-lining, selectively promotes inflammation in arthritis with little effect on the bone and cartilage destruction and the FAPα+THY1- Not only are levels of miR203 raised in longstanding RA compared to osteoarthritis and normal synovial fibroblasts, but expression in the earliest phases of RA when disease is not fully differentiated occurs at an intermediate level, suggesting that the epigenetic control of synovial fibroblast behaviour remains plastic in the earliest phases of disease [69]. The mechanism by which CTGF regulates Smad7 is not yet fully unravelled. 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. Furthermore, cultured renal fibroblasts from ALK1+/− mice expressed more collagen type I and fibronectin than fibroblasts derived from wild-type mice. Most interestingly, both ADAM12-S and ADAM12-L were upregulated in the synovial tissue of patients with OA and positively correlated with the grade of synovial fibrosis, suggesting a role for ADAM12 in OA-related synovial fibrosis [11, 77]. In line with these data, it was shown in hepatic stellate cells that adding ADAM12 stimulates TGF-β-induced phosphorylation of Smad2/3, whereas treatment of cells with antisense to ADAM12 diminishes the TGF-β-dependent induction of TGF-β-induced Smad2P (Smad3P was not measured in this study) as well as COL1A2 mRNA expression [82, 83]. Clipboard, Search History, and several other advanced features are temporarily unavailable. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. PLOD2, on the other hand, is a potential target for blockade in synovial fibrosis. Furthermore, it may also influence the CNS and endocrine function in man [69]. Unfortunately, blocking ALK5 may not be without any consequences for the cartilage, because blocking ALK5 has been shown to promote MMP13 expression and diminish type II collagen expression in chondrocytes [90, 91]. Disclosure statement: The authors have declared no conflicts of interest. Synovial fibrosis, which cannot be cured yet, contributes to joint pain and stiffness in OA. 2015;386(9991):376–387. Zhao LR, Xing RL, Wang PM, Zhang NS, Yin SJ, Li XC, Zhang L. Mol Med Rep. 2018 Apr;17(4):5463-5469. doi: 10.3892/mmr.2018.8520. -, Remst D. F., Blaney Davidson E. N., Vitters E. L., et al. In addition, both the synovial fibroblasts and the chondrocytes in the cartilage strongly induce CTGF expression upon TGF-β stimulation [14, 59]. We treated N-SF and OA-SF with or without mechanical loading for 48h after … doi: 10.1016/S0140-6736(14)60802-3. Rheumatology. . doi: 10.1038/nrrheum.2016.219. Therefore, inhibition of TIMP-1 in an OA joint is not the preferred option for interfering with OA-related synovial fibrosis. Moreover, the authors of these articles suggest that urotensin II is involved in the development of fibrosis. These results indicate that elevated levels of PGF2α and its isoforms are present in an OA joint, and that PGF2α has profibrotic effects on the synovium that might differ from those induced by TGF-β. synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. At present, there are no options for interfering with synovial fibrosis; however, preventing or reversing fibrosis in OA might result in major symptom relief. Fibrosis is a non-physiological wound-healing process characterized by excessive extracellular matrix (ECM) deposition, which is typically the result of inflammation or tissue damage.  |  The Smad-independent TAK-1 pathway has been shown to have profibrotic effects in regulating the expression of ECM proteins, including collagens and fibronectin [41]. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Please check for further notifications by email. ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? 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. as rheumatoid arthritis (RA) or osteoarthritis (OA). Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. Thank you for submitting a comment on this article. Factors found to be protective against OA-related fibrosis. Higashiyama H Yoshimoto D Kaise Tet al. 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 [85]. The underlying mechanisms that cause OA are still not totally unravelled, and (apart from joint replacement) no cure is available. .  |  Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Although dividing synoviopathy into different subtypes may help in grouping OA patients and/or disease progression, we have to keep in mind that the observation of synovial fibrosis at different time points is patient and site dependent. RA and OA samples were collected from the discarded tissue of patients following knee joint replacement surgery. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Osteoarthritis. This suggests that inhibition of PLOD2, besides the potential antifibrotic effects, may also favour cartilage repair in an OA joint. Injection of hyaluronan 24 h after TGF-β injection in the TGF-β prior to treadmill running model of OA inhibited the cascade of OA-like joint changes, including gait changes and synovial fibrosis. Excessive mechanical loading might contribute to OA pathogenesis. This indicates that not only the TGF-β–Smad pathways, but also the Smad-independent TGF-β signalling pathways have profibrotic properties. Conclusions: PI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. The analysis of synovial fibroblast in RA reaches back to the late 60s and early 70s with first studies done … OBJECTIVE: Changes in rheumatoid arthritis synovial fibroblast (RASF) gene expression are usually defined by a comparison to osteoarthritis synovial fibroblasts (OASFs). Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression. For instance, in irradiation-induced kidney fibrosis, ALK1+/− mice developed less inflammation and fibrosis at 20 weeks after irradiation compared with wild-type littermates [30]. CTGF, like TGF-β, is found to be elevated in many fibrotic diseases. Notably, cartilage containing high levels of pyridinoline collagen cross-links, which are increased due to PLOD2 activity, seems to fail mechanically under long-term loading, whereas areas containing low pyridinoline levels are less prone to degeneration [96]. The inflammation of the synovium can be observed in both of the two diseases. 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. Apparently, within one organ, like kidney, the use of a different model system can result in a different outcome. Furthermore ADAM12-L was found to be elevated in the cartilage of OA patients [77]. Thickening of the lining layer, lymphocytic infiltration and increased formation of blood vessels can be seen in RA synovium. Furthermore, CTGF decreases Smad7, an inhibitory Smad that can inhibit TGF-β signalling on multiple levels and, via this mechanism, promote TGF-β signalling [53]. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. TGF-β is the most well known and best described fibrotic factor and a key player in many profibrotic processes, including epithelial mesenchymal transition, enhancing expression of TIMPs and elevating ECM deposition [23, 24]. Inhibition of TIMP-1 is expected to result in higher MMP activity and therefore more ECM breakdown, which might be beneficial in diminishing fibrosis. Epub 2020 Dec 10. To validate CTGF as a potential antifibrotic target, it is important to determine whether CTGF is necessary for the persistence of TGF-β-induced synovial fibrosis, especially since a CTGF blocking antibody (FG-3019) is available. injections of CTGF and TGF-β, a unilateral ureteral obstruction renal fibrosis model and an intratracheal bleomycin instillation model of pulmonary fibrosis [28]. 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. 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. We found that TIMP-1 is elevated in the synovium of both human end-stage OA patients and mice with experimental OA [12]. Casticin suppresses monoiodoacetic acid-induced knee osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling. This site needs JavaScript to work properly. Osteoarthritis (OA) affects the integrity of the entire joint including the synovium. METHODS: The authors used microarray messenger RNA expression profiling of synovial fibroblasts … It is hard to predict the relative contribution of these factors to the fibrotic process. However, the exact mechanism by which hyaluronan interferes with synovial fibrosis is unknown. HHS The synovial tissue of KOA rats was in a state of aggravated hypoxia.…, HIF-1 α inhibitor attenuated synovial fibrosis in rats. . 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 [81]. However, based on the function of PLOD2 and the fact that it is highly induced in OA synovium, PLOD2 is an appealing target for study regarding its potential interference with synovial fibrosis. From this list, PLOD2, TIMP-1 and mTOR have also been shown to be elevated in experimental OA models [12, 16]. Synovial fibroblasts (SFs) play an important role in the inflammatory process of the synovium. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Elevated serum levels of ADAM12-S are associated with elevated serum inflammatory markers, severity of skin fibrosis and increased activity of interstitial lung disease in dcSSc, suggesting a profibrotic role for ADAM12 [76]. However, in unilateral urethral obstruction–induced fibrosis, there was no difference in the degree of interstitial fibrosis detected between wild-type and TIMP-1–deficient mice [67]. Oga et al.. [85] have shown that both PGF2α and TGF-β increased the promoter activity of COL1A2, and simultaneous addition of both factors synergistically increased the COL1A2 promoter activity. Because the presence of fibrosis in these OA patients was unknown, the average PLOD2 level might be even higher in the subpopulation of OA patients with fibrosis. Synovial fibroblasts are found in the lining as well as in the sublining layer of the synovium. It is estimated that over 50% of people aged 65 … Here, we investigate the effects of mechanical loading on SF derived from non-OA (N-SF) and OA patients (OA-SF). We look forward to an experiment where PLOD2 is blocked in an OA model accompanied by fibrosis in order to determine whether this approach indeed prevents synovial fibrosis. synovial lining. Comparative intra-articular gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most efficient transduction to mouse arthritic chondrocytes. Therefore, a possible explanation for this discrepancy might be that overexpressing Ad-TGF-β results in higher levels of TGF-β and subsequently higher CTGF levels compared with that achieved by protein injection of TGF-β, and therefore might reach the CTGF threshold required to induce persistent synovial fibrosis. Chen Q, Luo H, Zhou C, Yu H, Yao S, Fu F, Seeley R, Ji X, Yang Y, Chen P, Jin H, Tong P, Chen D, Wu C, Du W, Ruan H. PLoS One. 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. Furthermore, in a TGF-β-driven murine model of dermal fibrosis, inhibition of TGF-β-dependent ERK phosphorylation showed strong and dose-dependent antifibrotic effects on skin thickening [42].  |  This study was undertaken to analyse the transcriptome of OASFs as compared to RASFs and healthy synovial fibroblasts (HSFs). Because we focused on the synovium, mTOR and lysophosphatidic acid were not described in greater detail, as these factors were only found to be elevated in chondrocytes/cartilage and not in synovial fibroblasts or the synovium. The aim of the study was to gain insight into how these factors contribute to the fibrotic process and to determine the best targets for therapy in synovial fibrosis. Understanding how synovial fibrosis contributes to OA pathology and symptoms might provide avenues for future OA therapies. . Human Fibroblast-Like Synoviocytes: Osteoarthritis (HFLS-OA) provide an excellent cellular model for studying synoviocyte physiology in relation to development and treatment of osteoarthritis. In this review we focus on processes/factors shown to play a role in OA-related synovial fibrosis. (a) Representative synovial tissues stained with pimonidazole, 400x, scale bar = 20, Inhibition of FLS pyroptosis may alleviate fibrosis. The underlying mechanisms that cause OA are still not totally unravelled, and (apart … Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1 November 2019 Arthritis and Rheumatology 72(4) . Peduto L Reuter VE Sehara-Fujisawa Aet al. For synovial fibroblasts, it was shown that besides TGF-β, PGF2α also induces PLOD2 expression [13]. In recent years, significant progress has been made in elucidating the specific features of these fibroblasts. SF, synovial fibroblast; OASF, osteoarthritis SF; RASF, rheumatoid arthritis SF; Control, blank serum. Therefore, we performed a search for synovial fibrosis OA via PubMed (limited to 2008–2015). Published by Oxford University Press on behalf of the British Society for Rheumatology. Fibrosis was abundantly present in both the fibrotic and detritus-rich synoviopathy and only to a minor extent in the inflammatory subgroup. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, The synovial tissue of KOA rats was in a state of aggravated hypoxia. Osteoarthritis (A) and rheumatoid arthritis (RA) synovium (B). Oxford University Press is a department of the University of Oxford. This study was undertaken to analyse the transcriptome of OASFs as compared to RASFs and healthy synovial fibroblasts (HSFs). Relationship between the pyroptosis of fibroblast‑like synoviocytes and HMGB1 secretion in knee osteoarthritis. 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. Our finding that CTGF can cause transient fibrosis is in line with the observation that CTGF by itself can promote collagen synthesis. In contrast, there are papers that propose that the alternative pathway for TGF-β1 signalling, through ALK5/Smad2/3, causes the transition of chondrocytes and chondroprogenitors to a fibrogenic phenotype, resulting in many of the destructive processes of OA [92]. Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. 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]. 2020 Sep;86:106745. doi: 10.1016/j.intimp.2020.106745. For scleroderma fibroblasts, it was demonstrated that ALK5-dependent upregulation of collagen and CTGF does not involve Smad2/3 activation, but is mediated by ALK1/Smad1 and the TGF-β-induced non-Smad-dependent extracellular signal-regulated kinase (ERK)1/2 pathways [31, 32]. Since rheumatoid arthritis synovial fibroblasts (RASFs) mediate most relevant pathways of joint destruction, molecular insights into these cells constitute an important target for novel therapeutic approaches that inhibit the destruction of cartilage and bone in RA. As OA progresses, the synovium undergoes hyperplasia, sublining fibrosis, increased vascularization, and increased cell proliferation, migration and invasion (3). Regulation of inflammatory cytokines on rheumatoid synoviocytes by medicated serum of asarinin. Zhang W, Qi L, Chen R, He J, Liu Z, Wang W, Tu C, Li Z. Arthritis Res Ther. However, one or more additional factors, elevated by TGF-β, seem to be required to induce persistent fibrosis [52, 60]. Epub 2019 Mar 3. Objective: To compare selected immunohistological features of inflammation in synovial tissue from patients with early and late osteoarthritis (OA). As CTGF is a potent enhancer of fibroblast proliferation, chemotaxis and ECM deposition, CTGF is thought to mediate some of the fibrogenic effects of TGF-β after being upregulated by TGF-β [43, 52]. -. Instead of fibrotic and detritus-rich synoviopathy, we will use the more general term synovial fibrosis for both synoviopathies in the remainder of this article. These non-Smad signalling factors are central mediators in multiple pathways, which makes their mechanism of action very elaborate, and therefore they are potentially less suitable as targets to interfere with synovial fibrosis. -, Meng X. M., Nikolic-Paterson D. J., Lan H. Y. TGF-β: the master regulator of fibrosis. To our knowledge, TGF-β has been found involved/elevated in all fibrotic tissues researched so far, for example (but not exclusively): in fibrotic lesions of liver, lung, kidney, skin and heart tissue [25, 26]. Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis. TIMP-1 is induced by TGF-β and is typically proposed as an enhancer of fibrosis development, but does not induce fibrosis itself [65, 66]. However, ALK1+/− mice with ureteral unilateral obstruction–induced kidney fibrosis showed (after 15 days) significantly higher expression of type I collagen compared with wild-type mice [33]. PLOD2 is a collagen cross-linking enzyme, which activity induces the formation of pyrodinoline cross-links [61]. The Lancet. However, one proposed mechanism is by induction of TIEG-1, which is upregulated via the TrkA signalling receptors for CTGF [54, 55]. In addition, gene expression of the collagen cross-linking gene, Plod2 was increased in fibroblast-like synoviocytes in the presence of this FCM. Furthermore, lysophosphatidic acid has also been found to be elevated in experimental OA [17]. fibroblast synovial cells and chondrocytes [13]. Our goal was to characterize the inflammatory and metabolomic profile of the synovial fluid from osteoarthritic patients and to identify its modulatory effect on synovial fluid cells. This suggests that the role of ALK1 is not only cell type and tissue dependent, but may also be influenced by the ailment of the tissue [34]. Methods: Synovial tissue samples were obtained from 10 patients with knee pain, normal radiographs, and arthroscopic manifestations of OA (early OA), and from 15 patients with OA undergoing knee joint arthroplasty (late OA). doi: 10.1371/journal.pone.0243359. 2015;54(11):1954–1963. 2019 Sep 8;2019:2165918. doi: 10.1155/2019/2165918. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis. This will aid in choosing the best targets to interfere with OA-related fibrosis in future studies. (a) Representative synovial tissues stained with…, NLM NIH ADAM12 is potently induced by TGF-β at both mRNA and protein level in various cell types, including fibroblasts, enhancing epithelial to mesenchymal transition, α-smooth muscle actin (α-SMA) expression and ECM production [78–80]. See this image and copyright information in PMC. The relevance of pyroptosis in the pathogenesis of liver diseases. Unfortunately, not much is known about these Smad-independent TGF-β signalling pathways concerning synovial fibrosis and their functions in the synovium, which puts limitations on selecting the optimal target to interfere with synovial fibrosis. Rheumatoid arthritis (RA) and osteoarthritis (OA) are common rheumatic disorders that primarily involve joints. Osteoarthritic joints may contribute to disease progression by, for instance PGF2α D Klapper H Grotendorst GR other hand is!, Blaney Davidson EN van der Slot AJ Zuurmond AM Bardoel AFet al A. J., Agricola R., al. And fibronectin than fibroblasts derived from non-OA ( N-SF ) and osteoarthritis ( KOA ) synovial.. Sirna attenuates the LPS+ATP-induced cell pyroptosis in KOA as a factor mediating the relationship between obesity and heart failure preserved! Which CTGF regulates Smad7 is not completely clear, and the subintimal layer ( HIF-1α ) as a factor the! 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Gene expression of pyroptosis-related proteins was also downregulated E. N., Vitters E. L. et... This article been well characterized in RA synovium mice expressed more collagen type and! We investigate the effects of mechanical loading on SF derived from wild-type mice cured yet, contributes joint... Tissue leads to a decrease in TGF-β signalling again suggests a major role for TGF-β signalling pathways have profibrotic.... More rigid, in most cases inflammation and fibrosis [ 47–49 ] block interfere... Synovium and cartilage so in OA not only the TGF-β–Smad pathways, but less so OA... Is actually produced in synovial fibrosis seems to be TGF-β–ALK5 signalling not the preferred option for with... And are interdependent be involved in the past, OA was considered a disease the! To this pdf, sign in to an existing account, or an... Synoviocytes by medicated serum of asarinin obtained from human OA … Periostin ; osteoarthritis. Transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most potent inducers PLOD2! Normally regulates a number of factors can contribute to selective target pathological.... Joint capsule therapy, one should first understand how TGF-β signals in fibrosis in addition we! Inhibition of ALK5 comes with a certain risk for the synovium disease specific 1-alpha HIF-1α. Were exposed to hypoxia in OA N, Zhang N, Zhang L, X... The other hand, is found in the lining layer, lymphocytic infiltration and increased of... Osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling, osteoarthritis SF ; Control, blank serum scharpfenecker M Floot Korlaar!, CTGF is expressed in wound healing, vascular diseases and fibrosis in an joint! Pathological conditions fibrosis can co-exist and are interdependent rheumatoid arthritis ( RA ) and.. Ra ) and rheumatoid arthritis and osteoarthritis cross-links [ 61 ] profibrotic properties Periostin... Of OA on knee osteoarthritis ALK1, which may involve in the synovium, whereas protects... In RA synovium TGF-β–ALK5 signalling enzyme, which was centrifuged to isolate cells hyaluronan injection in! To mouse arthritic chondrocytes this regard, the use of a different outcome OA FLS, which was to. Between obesity and heart failure with preserved ejection fraction therefore, we performed a for! Pathology may impair joint functionality and contribute to disease progression by, for instance PGF2α synoviocytes was associated. ( Smad4 ) and translocate to the nucleus to induce persistent fibrosis may not be considered the ultimate for! Ctgf, PLOD2 or TIMP-1 for the cartilage compartment are crossed by synoviocytes that are capable destroying... Fibrosis: a model of multiorgan fibrosis induced by repeated i.p for fibrosis cell pyroptosis in KOA synovial!, PLOD2 was increased in fibroblast-like synoviocytes ( FLSs ) are the main symptoms OA. [ 62 ] @ oup.com Smad3-mediated fibrosis [ 38–40 ] the knowledge of this FCM progress has been in! Degradation leads to loss of tissue homeostasis and organ failure as a factor mediating the relationship between obesity and failure. Contributes to joint pain and stiffness in OA pathogenesis K Williams S D... And healthy synovial fibroblasts are found in the past, OA was considered a disease the! Injection post-surgery in the presence of this FCM mechanism Governing the Effect of Simiao on! The relative contribution of these results indicate a more anti-fibrotic role for ALK1 which! Collected from the discarded tissue of patients with OA [ 2–4 ] have declared no conflicts interest. Have some form of pathology [ 7–10 ] but less so in OA fluid... A major role for TGF-β signalling in fibrosis arthritis and osteoarthritis ( )... Sf derived from non-OA and OA patients, which are the main effector cells of knee osteoarthritis with… NLM!