{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:11:55Z","timestamp":1787163115858,"version":"build-2736575974"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2012,9,28]],"date-time":"2012-09-28T00:00:00Z","timestamp":1348790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify mechanisms by which Smad3 maintains articular cartilage and prevents osteoarthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A combination of in vivo and in vitro approaches was used to test the hypothesis that Smad3 represses Runx2\u2010inducible gene expression to prevent articular cartilage degeneration. Col2\u2010Cre;Smad3\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice allowed study of the chondrocyte\u2010intrinsic role of Smad3 independently of its role in the perichondrium or other tissues. Primary articular cartilage chondrocytes from Smad3\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice and ATDC5 chondroprogenitor cells were used to evaluate Smad3 and Runx2 regulation of matrix metalloproteinase 13 (MMP\u201013) messenger RNA (mRNA) and protein expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Chondrocyte\u2010specific reduction of Smad3 caused progressive articular cartilage degeneration due to imbalanced cartilage matrix synthesis and degradation. In addition to reduced type II collagen mRNA expression, articular cartilage from Col2\u2010Cre;Smad3\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice was severely deficient in type II collagen and aggrecan protein due to excessive MMP\u201013\u2013mediated proteolysis of these key cartilage matrix constituents. Normally, transforming growth factor \u03b2 (TGF\u03b2) signals through Smad3 to confer a rapid and dynamic repression of Runx2\u2010inducible MMP\u201013 expression. However, we found that in the absence of Smad3, TGF\u03b2 signals through p38 and Runx2 to induce MMP\u201013 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings elucidate a mechanism by which Smad3 mutations in humans and mice cause cartilage degeneration and osteoarthritis. Specifically, Smad3 maintains the balance between cartilage matrix synthesis and degradation by inducing type II collagen expression and repressing Runx2\u2010inducible MMP\u201013 expression. Selective activation of TGF\u03b2 signaling through Smad3, rather than p38, may help to restore the balance between matrix synthesis and proteolysis that is lost in osteoarthritis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.34566","type":"journal-article","created":{"date-parts":[[2012,9,30]],"date-time":"2012-09-30T14:14:59Z","timestamp":1349014499000},"page":"3278-3289","source":"Crossref","is-referenced-by-count":123,"title":["Chondrocyte\u2010intrinsic Smad3 represses Runx2\u2010inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis"],"prefix":"10.1002","volume":"64","author":[{"given":"Carol G.","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Thuillier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily 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