Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

作者：Daisuke Hamada, Robert Maynard, Eric M. Schott, Christopher J. Drinkwater, John Ketz, Stephen L. Kates, Jennifer H. Jonason, Matthew J. Hilton, Michael J. Zuscik, Robert A. Mooney · 发表于：Arthritis & Rheumatology · 年份：2015 · DOI：10.1002/art.39561 · 被引用次数：132 · 研究领域：Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases、Bone health and osteoporosis research

OBJECTIVE: Obesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity-associated 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. METHODS: The effects of TNF and insulin on catabolic gene expression were determined in fibroblast-like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high-fat (HF) diet-fed obese mice with type 2 DM and TNF-knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM. RESULTS: Insulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose-dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF-knockout mice, increases in osteophyte formation and synovia...