Abstract
Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.
Highlights
Osteoarthritis (OA) is one of the most common musculoskeletal disorders that affect millions of individuals
In synovial fluid (SF), we observed that the increase of leptin levels in the high-fat diet (HFD) group was from W15 to W27, not from W5 compared to the control (NC) or untreated (CON) group (Figure 2(b))
For the HFD group, a significant positive correlation of leptin levels between the serum and SF was observed at W15 (R2 = 0:8019, P = 0:0399) and W27 (R2 = 0:9613, P = 0:0033) which is consistent with the result of Figure 2(b) (Figures 2(c)–2(e))
Summary
Osteoarthritis (OA) is one of the most common musculoskeletal disorders that affect millions of individuals It is characterized structurally by degradation of the articular cartilage and subchondral bone remodeling, accompanied by joint malfunction, chronic pain, and loss of function [1]. It is worth noting that Griffin et al proved that a lack of leptin does not lead to an increase in the incidence of spontaneous OA in a mouse model, its body weight is extremely high, indicating that the loss of leptin signaling may protect the human body from the progress of OA [4], which has drawn our attention whether leptin plays an initial role in the pathogenesis of obesity-related OA or it is just a driver of OA progress, and by what mechanism does leptin promote OA
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