The role of adipose secreted cytokines in driving the pathological changes in osteoarthritis

Philp, Ashleigh M. (2017). The role of adipose secreted cytokines in driving the pathological changes in osteoarthritis. University of Birmingham. Ph.D.

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Abstract

Adipose secreted cytokines are thought to contribute to pro-inflammatory state seen commonly in obese individuals, providing a potential metabolic link between obesity and osteoarthritis. The aim of this study is to further our understanding of the role of adipokines within OA by examining the serum and joint fluid adipokine expression profiles in relation to disease severity, BMI, and joint tissue turnover markers. The result of this study show that subchondral bone from overweight/obese hip OA patients exhibited reduced trabecular thickness, increased bone surface/bone volume ratio and an increase in the type I collagen α1/α2 ratio, compared to normal-weight hip OA patients. The serum concentration of resistin was higher in overweight/obese OA patients, compared to normal-weight OA patients (12740 vs 9818pg/mL respectively; p<0.05). Stimulation of normal-weight bone explant with recombinant resistin resulted in a 2.4 fold increase in type I collagen α1/α2 ratio (1.6:1 vs 3.8:1, p<0.01). Stimulation of primary OA osteoblasts with resistin increased Wnt signalling activation, osteoblast metabolic activity, and bone nodule formation. In addition, visfatin was elevated in the synovial fluid and in isolated synovial fibroblasts of obese hip OA patients compared to normal-weight patients. In cartilage, visfatin increased the production of 15 pro-inflammatory cytokines and chemokines, with significant increases in IL-6, CCL4, MCP-1 and in CCL20 compared to the media only control (>7 fold, 20-fold, 4-fold and 7-fold respectively). Visfatin significantly increased in catabolic proteases including MMP-1 (4-fold), MMP-2 (3-fold), MMP-3 (3-fold), MMP-7 (2.2-fold), MMP-8 (1.3-fold), MMP-9 (1.2-fold), MMP-10 (1.5-fold), and MMP-13 (5-fold) and localised to areas of cartilage damage.
Targeted inhibition of adipokine signalling could therefore be a rewarding strategy for developing a novel therapeutic.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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