{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:01:37Z","timestamp":1791356497915,"version":"4.3.1"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2004,1,9]],"date-time":"2004-01-09T00:00:00Z","timestamp":1073606400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2004,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate in vivo and in vitro whether macrophages have an intermediate role in transforming growth factor \u03b2 (TGF\u03b2)\u2013induced osteophyte formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vivo, synovial lining macrophages were selectively depleted by injection of clodronate\u2010laden liposomes 7 days prior to injection of 20 ng or 200 ng of TGF\u03b2 into murine knee joints 3 times, on alternate days. Total knee joint sections were obtained on day 7 after the last injection and stained with Safranin O. Production of bone morphogenetic protein 2 (BMP\u20102) and BMP\u20104 was determined by immunolocalization. The interaction between murine macrophages and mesenchymal cells (precursors with chondrogenic potential) was studied in vitro using a Transwell system in which RAW macrophages were cocultured with C3H10T1\/2 mesenchymal cells. Spheroid neocartilage formation was quantified microscopically after staining with May\u2010Gr\u00fcnwald\u2013Giemsa.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Triple injections of 20 ng or 200 ng of TGF\u03b2 into normal murine knee joints induced significant osteophyte formation at the lateral and medial sites of the patella and femur on day 7 after the last injection. Strikingly, removal of synovial lining macrophages prior to TGF\u03b2 injection resulted in a drastic reduction of osteophyte formation (by 70% and 64% after injection of 20 ng and 200 ng of TGF\u03b2, respectively). Synovial lining cells produced BMP\u20102 and BMP\u20104 after TGF\u03b2 stimulation, whereas BMP\u20102 and BMP\u20104 were absent in the synovial tissue after macrophage depletion. In vitro, clustering and spheroid formation of C3H10T1\/2 was induced by TGF\u03b2 concentrations of &gt;1 ng\/ml. However, in the Transwell system, in the presence of murine macrophages, 0.5 ng\/ml of TGF\u03b2 was very effective in generating large spheroids, suggestive of macrophage\u2010derived (co)factors. In coculture supernatants, TGF\u03b2 concentrations were not elevated in the presence of macrophages, indicating generation of other growth factors involved in spheroid formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that macrophages are crucial intermediate factors in osteophyte formation induced by TGF\u03b2, probably by inducing other chondrogenic signals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.11422","type":"journal-article","created":{"date-parts":[[2004,1,13]],"date-time":"2004-01-13T07:02:17Z","timestamp":1073977337000},"page":"103-111","source":"Crossref","is-referenced-by-count":164,"title":["Crucial role of synovial lining macrophages in the promotion of transforming growth factor \u03b2\u2013mediated osteophyte formation"],"prefix":"10.1002","volume":"50","author":[{"given":"P. L. E. 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