gms | German Medical Science

Objectives: Growing evidence suggest that not only mechanical overload but also systemic metabolic factors contribute to articular cartilage degradation in obesity. The role of adipokines in this context remains incompletely understood. In order to better understand the distinct molecular mechanisms that contribute to knee OA in obesity, here we analyze the expression of various adipokines in intra- and extra-articular tissues in patients with end-stage knee OA, stratified according to BMI < 25 and BMI > 35, and correlate the adipokine expression with cartilage degeneration markers.

Methods: Blood serum, s.c. fat, synovial fluid, synovium and articular cartilage were obtained from 30 TKA patients (primary OA). BMI ranged from 20.1 to 37.8 including 5 individuals with < 25 and 10 individuals with BMI > 35. Samples were snap frozen within 3 minutes. Cartilage was obtained from the medial compartment. Total RNA was isolated and qRT-PCR TaqMan gene expression analysis was performed for the adipokines leptin, adiponectin, visfatin, resistin, the inflammatory markers TNF-alpha, IL6 and IL1-beta, the cartilage degradation and hypertrophy markers Col2a, ADAMTS5, ColXa and MMP13 as well as the nuclear receptors liver X receptors alpha and beta (LXR alpha, beta). Protein levels of adipokines and inflammatory markers in serum and synovial fluid were measured by ELISA.

Results and Conclusion: There was a significant relationship of BMI (< 25 vs >35) with the expression of inflammatory markers in s.c. adipose tissue (TNF-alpha p=0.012, IL1-beta p=0.004, IL6 p=0.03), confirming adipose tissue inflammation in obesity. In contrast to the inflammatory markers TNF-alpha and IL1-beta that were not detectable in serum or synovial fluid, the expression levels of adipokines in s.c. fat were reflected in both serum and synovial fluid (lower adiponectin levels in serum (p<0.05) and higher leptin levels (p<0.05, p< 0.01) with BMI >35). Also gene expression of leptin in s.c. fat was significantly higher in obese patients (BMI>35). There were no differences in adipokine expression in articular cartilage or synovial tissue, indicating that adipose tissue inflammation and obesity-induced altered extra-articular adipokine expression has a direct effect on the intra-articular milieu via alteration of synovial fluid protein composition. Interestingly, BMI correlated significantly with ADAMTS5 (p=0.0001) but not with COL2, COLXa and MMP13 expression, suggesting a potential direct and specific effect of adipokines on ADAMTS5 expression. In addition, there was an up-regulation of the pharmacologically targetable, lipid activated nuclear receptor LXR beta in obese cartilage (p=0.01). Taken together, in obese patients with OA, distinct molecular mechanisms may offer therapeutic options for pharmacological interventions such as targeting nuclear receptor signaling.