Leptin Induced TLR4 Expression via the JAK2‐STAT3 Pathway in Obesity‐Related Osteoarthritis

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.

Stat3 Signaling Pathway: A Future Therapeutic Target for Bone-Related Diseases

“…Leptin is the most secreted adipokine in white adipose tissue and it also seems to trigger obesity-related OA via Stat3 ( Cordero-Barreal et al, 2021 ). Elevated leptin in serum induces activation of Stat3 in cartilage and leads to pathological activation of CD14/TLR4, which further provokes obesity-associated inflammation and MMP-13 expression ( Jiang et al, 2021 ). Analogously, the myeloid-derived growth factor (MYDGF) increases Stat3 phosphorylation on S727 ( Xu et al, 2022 ).…”

The Effect of Leptin on the Blood Hormonal Profile (Cortisol, Insulin, Thyroid Hormones) of the Ewe in Acute Inflammation in Two Different Photoperiodical Conditions

“…Although we did not find any article about the effect of leptin on TLR4 expression in the pancreas, Jiang et al [ 51 ] observed that leptin induces TLR4 expression via the JAK2-STAT3 pathway in obesity-related osteoarthritis, so the leptin effect on TLR4 expression in other organs cannot be excluded. Moreover, Jiang et al [ 51 ] also presented that the silencing of the suppressor of cytokine signaling 3 (SOC3, the main inhibitor of leptin action) significantly influenced TLR4 expression, which can emphasize the leptin-TLR4 dependence. Certainly, the obtained results show that the leptin-insulin-acute inflammation relationship is complicated and requires further intensive research.…”

Hypoxia-Preconditioned Extracellular Vesicles from Mesenchymal Stem Cells Improve Cartilage Repair in Osteoarthritis

“…STAT3 forms part of the JAK-STAT signal cascade, which is the basis of many cytokine receptor signal transduction mechanisms [33]. The JAK-STAT3 signaling pathway is involved in metabolism, proliferation, apoptosis, and inflammation in OA [34]. MAPK1, also known as ERK, belongs to the MAPK family and is related to various cell processes, including proliferation, differentiation, transcription modulation, and development.…”