Ctsk + Osteoclasts Orchestrate Condylar Morphogenesis via Hypoxic Lysosome.

This article focuses on the role of cathepsin K–positive (ctsk⁺) osteoclasts and hypoxia-inducible factor-1α (HIF-1α) in mandibular condylar cartilage (MCC) morphogenesis and subchondral bone remodeling. Using genetic ablation of ctsk⁺ cells in diphtheria toxin receptor (DTR) transgenic mice and conditional knockout of HIF-1α in ctsk⁺ osteoclasts, the study demonstrates that ctsk⁺ osteoclasts suppress chondrocyte proliferation and premature hypertrophy while regulating cartilage degradation and subchondral osteogenesis. HIF-1α deficiency in these osteoclasts disrupts lysosomal biogenesis and ruffled border ultrastructure via the TSC2-mTORC1-TFEB signaling axis, impairing osteoclast function under hypoxic conditions and leading to abnormal cartilage accumulation followed by accelerated but disorganized subchondral bone mineralization. These findings reveal a dual regulatory mechanism by which ctsk⁺ osteoclasts coordinate hypoxia-responsive cartilage-to-bone transition during condylar development.