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This study was undertaken to define the links between obesity\u2010associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of TNF and insulin on catabolic gene expression were determined in fibroblast\u2010like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high\u2010fat (HF) diet\u2013fed obese mice with type 2 DM and TNF\u2010knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Insulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose\u2010dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of <jats:italic>MMP1<\/jats:italic>, <jats:italic>MMP13,<\/jats:italic> and <jats:italic>ADAMTS4<\/jats:italic> by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by &gt;50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF\u2010knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin\u2010dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin resistance in patients with type 2 DM may impair this protective effect and promote the progression of OA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39561","type":"journal-article","created":{"date-parts":[[2015,12,29]],"date-time":"2015-12-29T11:22:55Z","timestamp":1451388175000},"page":"1392-1402","source":"Crossref","is-referenced-by-count":115,"title":["Suppressive Effects of Insulin on Tumor Necrosis Factor\u2013Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus"],"prefix":"10.1002","volume":"68","author":[{"given":"Daisuke","family":"Hamada","sequence":"first","affiliation":[{"name":"University of Rochester Medical Center Rochester New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Maynard","sequence":"additional","affiliation":[{"name":"University of Rochester Medical Center Rochester New 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