Serum Leptin Exacerbates Osteoarthritis by Promoting Subchondral Bone H-Type Vessel Angiogenesis via Activation of the PI3K/AKT Pathway.

Osteoarthritis (OA) is a common degenerative joint disease closely associated with obesity. Adipokines secreted by adipose tissue play critical roles in disease progression. This study focuses on the adipokine leptin and investigates its relationship with knee osteoarthritis. Analysis of subchondral bone tissue from OA patients revealed decreased leptin receptor expression, enhanced osteogenic activity, and a significant increase in H-type vessel number. Concurrently, serum leptin levels were markedly elevated in OA patients. Animal experiments further demonstrated that leptin-knockout obese mice exhibited significantly milder OA, reduced H-type vessel formation, and decreased osteogenic activity. In contrast, mice with high serum leptin levels showed more severe joint destruction and vascular hyperplasia. In vitro cell experiments indicated that leptin activates the PI3K/AKT signalling pathway in bone marrow mesenchymal stem cells (BMSCs), increasing the secretion of angiogenic factors such as VEGF and HIF-1α. Conditioned medium from leptin-treated BMSCs promoted tube formation and expression of H-type vessel markers (EMCN/CD31) in mouse umbilical vein endothelial cells. Inhibition of the PI3K pathway using Ly294002 in BMSCs or ZSTK474 in mice abolished leptin's effects. These results suggest that obesity-induced hyperleptinemia drives aberrant H-type vessel angiogenesis and active bone remodelling in subchondral bone via the PI3K/AKT pathway, thereby accelerating OA progression.