HIF-1α-centered metabolic reprogramming in osteoarthritis: cell type-specific effects and intercellular crosstalk...

Osteoarthritis (OA) is a systemic metabolic disorder characterized by cartilage degeneration and pathological changes in the "core functional cell populations" in the joints, i.e., chondrocytes, bone marrow mesenchymal stromal cells (BMSCs), and macrophages. In this review, we summarize the current evidence on HIF-1α-centered metabolic reprogramming in OA, with a focus on its cell type-specific effects in chondrocytes, BMSCs, and macrophages, and discuss how HIF-1α-associated intercellular crosstalk may contribute to cartilage degeneration, synovial inflammation, and impaired endogenous repair. While previous reviews mainly addressed HIF-1α-related hypoxia, glycolysis, mitochondrial dysfunction, inflammation, or therapeutic targeting as separate aspects of OA, this review takes a multicellular perspective to emphasize HIF-1α as a cell type-specific metabolic coordinator that connects chondrocyte degeneration, BMSC dysfunction, macrophage polarization, and metabolite-mediated intercellular communication within the OA microenvironment. These core functional cell populations directly regulate cartilage homeostasis, synovial inflammation, and endogenous repair. It is noted that although osteoblasts and osteoclasts are widely recognized as contributors to OA-related subchondral bone remodeling, they are not classified as core functional cell populations in this review due to their primarily restricted functions to bone metabolism-dominated remodeling within the subchondral bone compartment. Under hypoxic, inflammatory, and oxidative-stress conditions, hypoxia-inducible factor-1α (HIF-1α) regulates glycolysis, mitochondrial function, and inflammatory responses. Therefore, while activation to some extent can aid the response of chondrocytes and BMSCs to hypoxemia and induce tissue repair, over-activation is detrimental, leading to tissue damage and aging of BMSCs, as well as an inflammatory M1-like state in macrophages. Therefore, it is recommended that therapeutic strategies should avoid the general inhibition of HIF-1α but focus on cell-specific regulation and targeted intervention of metabolic nodes.