{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:33:38Z","timestamp":1789612418360,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006315","name":"ReumaNederland","doi-asserted-by":"publisher","award":["16-1-40"],"award-info":[{"award-number":["16-1-40"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-\u03b2 (TGF-\u03b2) signaling via SMAD2\/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-\u03b2 signaling via SMAD2\/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1\u03b2 and OA-synovium conditioned medium negated SMAD2\/3 transcriptional activity in chondrocytes. This inhibition of TGF-\u03b2 signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1\u03b2 was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2\/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.<\/jats:p>","DOI":"10.3390\/ijms22158124","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T10:47:46Z","timestamp":1627555666000},"page":"8124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Osteoarthritis-Related Inflammation Blocks TGF-\u03b2\u2019s Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2\/3 Linker Region"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-7537","authenticated-orcid":false,"given":"Nathalie","family":"Thielen","sequence":"first","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Neefjes","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renske","family":"Wiegertjes","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guus","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elly","family":"Vitters","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"van Beuningen","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Blaney Davidson","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marije","family":"Koenders","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van Lent","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fons","family":"van de Loo","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-4884","authenticated-orcid":false,"given":"Arjan","family":"van Caam","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van der Kraan","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud University Medical Center, 6500 MD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chow, Y.Y., and Chin, K.Y. (2020). The Role of Inflammation in the Pathogenesis of Osteoarthritis. Mediat. Inflamm., 2020.","DOI":"10.1155\/2020\/8293921"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.joca.2020.01.016","article-title":"Identifying effector molecules, cells, and cytokines of innate immunity in OA","volume":"28","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","article-title":"The role of synovitis in osteoarthritis pathogenesis","volume":"51","author":"Scanzello","year":"2012","journal-title":"Bone"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino1, M.A., Conaghan, P., le Bars, M., Baron, G., Grassi, W., Martin-Mola, E., Wakefield, R., Brasseur, J.-L., So, A., and Backhaus, M. (2005). EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part 1: Prevalence of inflammation in osteoarthritis. Ann. Rheum. Dis, 64, 1703\u20131709.","DOI":"10.1136\/ard.2005.037994"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1136\/ard.2011.150243","article-title":"Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: The MOST study","volume":"70","author":"Roemer","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/art.39438","article-title":"Brief Report: Association of Inflammation With Development of Erosions in Patients With Hand Osteoarthritis: A Prospective Ultrasonography Study","volume":"68","author":"Kortekaas","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/ar401","article-title":"Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: Integration of complex signaling pathways for the recruitment of gene-specific transcription factors","volume":"4","author":"Vincenti","year":"2002","journal-title":"Arthritis Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.joca.2006.01.008","article-title":"Activation by IL-1 of bovine articular chondrocytes in culture within a 3D collagen-based scaffold. An in vitro model to address the effect of compounds with therapeutic potential in osteoarthritis","volume":"14","author":"Cortial","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/art.23154","article-title":"Interleukin-1beta up-regulation of Smad7 via NF-kappaB activation in human chondrocytes","volume":"58","author":"Bauge","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.joca.2007.04.011","article-title":"Modulation of TGF-beta signaling by proinflammatory cytokines in articular chondrocytes","volume":"15","author":"Stokes","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Thielen, N.G.M., van der Kraan, P.M., and van Caam, A.P.M. (2019). TGFbeta\/BMP Signaling Pathway in Cartilage Homeostasis. Cells, 8.","DOI":"10.3390\/cells8090969"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1002\/art.34566","article-title":"Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis","volume":"64","author":"Chen","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.joca.2009.06.008","article-title":"TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: Modulation and integration of signaling pathways through receptor-Smads","volume":"17","author":"Blom","year":"2009","journal-title":"Osteoarthr. Cartil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/ar2896","article-title":"A role for age-related changes in TGFbeta signaling in aberrant chondrocyte differentiation and osteoarthritis","volume":"12","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1002\/art.22840","article-title":"Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes","volume":"56","author":"Bauge","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cytogfr.2013.06.002","article-title":"Smad phospho-isoforms direct context-dependent TGF-beta signaling","volume":"24","author":"Matsuzaki","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1016\/j.cellsig.2013.06.001","article-title":"Transforming growth factor-beta signalling: Role and consequences of Smad linker region phosphorylation","volume":"25","author":"Kamato","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","article-title":"TGF-beta signal transduction","volume":"67","author":"Massague","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/1521-1878(200103)23:3<223::AID-BIES1032>3.0.CO;2-U","article-title":"Structural insights on Smad function in TGFbeta signaling","volume":"23","author":"Shi","year":"2001","journal-title":"Bioessays"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/cr.2008.325","article-title":"Nucleocytoplasmic shuttling of Smad proteins","volume":"19","author":"Hill","year":"2009","journal-title":"Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40412","DOI":"10.1074\/jbc.M610172200","article-title":"Dephosphorylation of the linker regions of Smad1 and Smad2\/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways","volume":"281","author":"Sapkota","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1093\/carcin\/bgr172","article-title":"Smad phosphoisoform signaling specificity: The right place at the right time","volume":"32","author":"Matsuzaki","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"19808","DOI":"10.1074\/jbc.M109.016667","article-title":"A negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204","volume":"284","author":"Millet","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.joca.2011.12.003","article-title":"Chondrocyte hypertrophy and osteoarthritis: Role in initiation and progression of cartilage degeneration?","volume":"20","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"681","DOI":"10.2741\/1563","article-title":"TGF-beta signaling in chondrocytes","volume":"10","author":"Li","year":"2005","journal-title":"Front. Biosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/jor.23079","article-title":"Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-beta signaling","volume":"34","author":"Zhao","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.joca.2016.02.008","article-title":"Expression of TGFbeta-family signalling components in ageing cartilage: Age-related loss of TGFbeta and BMP receptors","volume":"24","author":"Madej","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a022061","DOI":"10.1101\/cshperspect.a022061","article-title":"TGF-beta Signaling from Receptors to Smads","volume":"8","author":"Hata","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.bbrc.2012.09.103","article-title":"Smad3 linker phosphorylation attenuates Smad3 transcriptional activity and TGF-beta1\/Smad3-induced epithelial-mesenchymal transition in renal epithelial cells","volume":"427","author":"Bae","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.1158\/0008-5472.CAN-14-0803","article-title":"Definition of smad3 phosphorylation events that affect malignant and metastatic behaviors in breast cancer cells","volume":"74","author":"Bae","year":"2014","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00018-010-0514-4","article-title":"Smad linker region phosphorylation in the regulation of extracellular matrix synthesis","volume":"68","author":"Burch","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.bbrc.2009.05.084","article-title":"The linker region of Smad2 mediates TGF-beta-dependent ERK2-induced collagen synthesis","volume":"386","author":"Li","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1002\/1529-0131(199812)41:12<2165::AID-ART11>3.0.CO;2-O","article-title":"Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis","volume":"41","author":"Melchiorri","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/art.1780350507","article-title":"The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function","volume":"35","author":"McCollum","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_35","first-page":"661","article-title":"p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondrocytes","volume":"17","author":"Radons","year":"2006","journal-title":"Int. J. Mol. Med."},{"key":"ref_36","first-page":"237","article-title":"The role of cytokines in osteoarthritis pathophysiology","volume":"39","author":"Fernandes","year":"2002","journal-title":"Biorheology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fphar.2017.00282","article-title":"Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1alpha and -1beta, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis","volume":"8","author":"Nasi","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.joca.2016.09.009","article-title":"Interleukin-1 is not involved in synovial inflammation and cartilage destruction in collagenase-induced osteoarthritis","volume":"25","author":"Blom","year":"2017","journal-title":"Osteoarthr. Cartil."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0014-4827(03)00180-0","article-title":"Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes","volume":"288","author":"Liacini","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Laavola, M., Leppanen, T., Hamalainen, M., Vuolteenaho, K., Moilanen, T., Nieminen, R., and Moilanen, E. (2018). IL-6 in Osteoarthritis: Effects of Pine Stilbenoids. Molecules, 24.","DOI":"10.3390\/molecules24010109"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/art.34315","article-title":"Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis","volume":"64","author":"Blom","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/iji.12015","article-title":"Association between CCL2 haplotypes and knee osteoarthritis","volume":"40","author":"Bidwell","year":"2013","journal-title":"Int. J. Immunogenet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/ten.tea.2011.0083","article-title":"Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells","volume":"18","author":"Heldens","year":"2012","journal-title":"Tissue Eng. Part A"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8296","DOI":"10.4049\/jimmunol.175.12.8296","article-title":"Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products","volume":"175","author":"Cecil","year":"2005","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.4049\/jimmunol.171.8.4406","article-title":"IL-8\/CXCL8 and growth-related oncogene alpha\/CXCL1 induce chondrocyte hypertrophic differentiation","volume":"171","author":"Merz","year":"2003","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1084\/jem.20062525","article-title":"Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification","volume":"204","author":"Morita","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1089\/ten.tea.2013.0553","article-title":"Inhibition of TAK1 and\/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions","volume":"20","author":"Vitters","year":"2014","journal-title":"Tissue Eng. Part A"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"65","DOI":"10.11005\/jbm.2018.25.2.65","article-title":"Differential Role of Transforming Growth Factor-beta in an Osteoarthritic or a Healthy Joint","volume":"25","year":"2018","journal-title":"J. Bone Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s13075-016-1038-6","article-title":"Inflammatory conditions partly impair the mechanically mediated activation of Smad2\/3 signaling in articular cartilage","volume":"18","author":"Madej","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/art.24151","article-title":"Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes","volume":"60","author":"Elshaier","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15018","DOI":"10.3748\/wjg.v20.i41.15018","article-title":"Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma","volume":"20","author":"Murata","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.cellsig.2016.05.002","article-title":"The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle","volume":"28","author":"Rostam","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1007\/s00018-010-0315-9","article-title":"TGF-beta stimulates biglycan synthesis via p38 and ERK phosphorylation of the linker region of Smad2","volume":"67","author":"Burch","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7212","DOI":"10.1038\/ncomms8212","article-title":"PI3K\/mTORC2 regulates TGF-beta\/Activin signalling by modulating Smad2\/3 activity via linker phosphorylation","volume":"6","author":"Yu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1016\/j.febslet.2012.02.001","article-title":"Phosphatases in SMAD regulation","volume":"586","author":"Bruce","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1089\/ten.tea.2008.0663","article-title":"ERK1\/2 activation induced by inflammatory cytokines compromises effective host tissue integration of engineered cartilage","volume":"15","author":"Djouad","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1172\/JCI119056","article-title":"Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes","volume":"98","author":"Geng","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e01659-18","DOI":"10.1128\/JVI.01659-18","article-title":"DUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus through Interleukin-1beta Signaling","volume":"93","author":"Manley","year":"2019","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.cellsig.2017.09.010","article-title":"Interleukin 1 beta-induced SMAD2\/3 linker modifications are TAK1 dependent and delay TGFbeta signaling in primary human mesenchymal stem cells","volume":"40","author":"Vitters","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1101\/gad.13.7.804","article-title":"A mechanism of repression of TGFbeta\/ Smad signaling by oncogenic Ras","volume":"13","author":"Kretzschmar","year":"1999","journal-title":"Genes Dev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15430\/JCP.2018.23.1.1","article-title":"Identification of Epithelial-Mesenchymal Transition-related Target Genes Induced by the Mutation of Smad3 Linker Phosphorylation","volume":"23","author":"Park","year":"2018","journal-title":"J. Cancer Prev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41598-020-80451-6","article-title":"Reporter gene comparison demonstrates interference of complex body fluids with secreted luciferase activity","volume":"11","author":"Neefjes","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1158\/0008-5472.CAN-06-4629","article-title":"Reversible Smad-dependent signaling between tumor suppression and oncogenesis","volume":"67","author":"Sekimoto","year":"2007","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.4161\/cc.20546","article-title":"Phospho-specific Smad3 signaling: Impact on breast oncogenesis","volume":"11","author":"Tarasewicz","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1016\/j.yexcr.2013.07.013","article-title":"Serine-204 in the linker region of Smad3 mediates the collagen-I response to TGF-beta in a cell phenotype-specific manner","volume":"319","author":"Browne","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.molcel.2009.09.043","article-title":"Ubiquitin ligase Nedd4L targets activated Smad2\/3 to limit TGF-beta signaling","volume":"36","author":"Gao","year":"2009","journal-title":"Mol. Cell."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00441-011-1190-x","article-title":"Role of Smads in TGFbeta signaling","volume":"347","author":"Heldin","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1074\/jbc.M403960200","article-title":"Role of Rho\/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo","volume":"280","author":"Kamaraju","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature02650","article-title":"Cyclin-dependent kinases regulate the antiproliferative function of Smads","volume":"430","author":"Matsuura","year":"2004","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"38365","DOI":"10.1074\/jbc.M607246200","article-title":"Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling","volume":"281","author":"Wrighton","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/cr.2008.327","article-title":"Phospho-control of TGF-beta superfamily signaling","volume":"19","author":"Wrighton","year":"2009","journal-title":"Cell Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"27271","DOI":"10.1074\/jbc.M503368200","article-title":"Transforming growth factor-beta-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors","volume":"280","author":"Hoffmann","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1091\/mbc.e04-11-1033","article-title":"Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3","volume":"16","author":"Benus","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/hep.22860","article-title":"Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma","volume":"49","author":"Nagata","year":"2009","journal-title":"Hepatology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/j.1755-148X.2009.00603.x","article-title":"SKI knockdown inhibits human melanoma tumor growth in vivo","volume":"22","author":"Chen","year":"2009","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_77","first-page":"1441","article-title":"Modulation of the transforming growth factor-beta1-induced Smad phosphorylation by the extracellular matrix receptor beta1-integrin","volume":"35","author":"Hamajima","year":"2009","journal-title":"Int. J. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1042\/BJ20100427","article-title":"Regulation of TGF-beta signalling by protein phosphatases","volume":"430","author":"Liu","year":"2010","journal-title":"Biochem. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"11940","DOI":"10.1073\/pnas.0605133103","article-title":"Unique players in the BMP pathway: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling","volume":"103","author":"Knockaert","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1021\/cb100357t","article-title":"Selective inactivation of a human neuronal silencing phosphatase by a small molecule inhibitor","volume":"6","author":"Zhang","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2174\/0929866525666171206114913","article-title":"Development of a Substrate Identification Method for Human Scp1 Phosphatase Using Phosphorylation Mimic Phage Display","volume":"25","author":"Otsubo","year":"2018","journal-title":"Protein Pept. Lett."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"7416","DOI":"10.1038\/sj.onc.1207981","article-title":"TGF-beta and HGF transmit the signals through JNK-dependent Smad2\/3 phosphorylation at the linker regions","volume":"23","author":"Mori","year":"2004","journal-title":"Oncogene"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Neefjes, M., van Caam, A.P.M., and van der Kraan, P.M. (2020). Transcription Factors in Cartilage Homeostasis and Osteoarthritis. Biology, 9.","DOI":"10.3390\/biology9090290"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3389\/fcell.2020.00081","article-title":"Significance of MEF2C and RUNX3 Regulation for Endochondral Differentiation of Human Mesenchymal Progenitor Cells","volume":"8","author":"Dreher","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00018-019-03266-3","article-title":"Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-beta signalling","volume":"77","author":"Kamato","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1002\/art.34529","article-title":"Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function","volume":"64","author":"Veenbergen","year":"2012","journal-title":"Arthritis Rheum."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8124\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:36:41Z","timestamp":1760164601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":86,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22158124"],"URL":"https:\/\/doi.org\/10.3390\/ijms22158124","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]}}}