{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:44:51Z","timestamp":1790891091506,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2005,9,2]],"date-time":"2005-09-02T00:00:00Z","timestamp":1125619200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2005,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate why bisphosphonates are less effective at preventing focal bone loss in rheumatoid arthritis (RA) patients than in those with generalized osteoporosis, and the mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The response of osteoclasts to alendronate (ALN) in tumor necrosis factor\u2013transgenic (TNF\u2010Tg) mice that develop erosive arthritis and in wild\u2010type littermates was studied. TNF\u2010Tg and wild\u2010type mice were given ALN, and the osteoclast numbers in the inflamed joints and in the long bones were compared. The expression levels of Bcl\u2010xL in the osteoclasts of TNF\u2010Tg and wild\u2010type mice were examined by immunostaining. The effect of overexpression of Bcl\u2010xL and Ets\u20102 proteins on ALN\u2010induced osteoclast apoptosis was determined using an in vitro osteoclast survival assay and retrovirus transfer approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ALN reduced osteoclast numbers in the metaphyses by 97%, but by only 46% in the adjacent inflamed joints. Bcl\u2010xL expression was markedly higher in osteoclasts in the joints than in those in the metaphyses of TNF\u2010Tg mice. Bcl\u2010xL or Ets\u20102 overexpression protected osteoclasts from ALN\u2010induced apoptosis, and TNF stimulated Bcl\u2010xL and Ets\u20102 expression in osteoclasts. Overexpression of Ets\u20102 increased Bcl\u2010xL messenger RNA in osteoclasts, while a dominant\u2010negative form of the Ets\u20102 blocked the protective effect of Bcl\u2010xL or TNF on ALN\u2010induced apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The reduced efficacy of bisphosphonates to stop bone erosion in the inflamed joints of RA patients may result from local high levels of TNF up\u2010regulating Ets\u20102 expression in osteoclasts, which in turn stimulates Bcl\u2010xL expression in them and reduces their susceptibility to bisphosphonate\u2010induced apoptosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.21236","type":"journal-article","created":{"date-parts":[[2005,9,2]],"date-time":"2005-09-02T16:18:18Z","timestamp":1125677898000},"page":"2708-2718","source":"Crossref","is-referenced-by-count":68,"title":["Tumor necrosis factor prevents alendronate\u2010induced osteoclast apoptosis in vivo by stimulating Bcl\u2010xL expression through Ets\u20102"],"prefix":"10.1002","volume":"52","author":[{"given":"Q.","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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