Ctsk⁺ Osteoclasts Orchestrate Condylar Morphogenesis via Hypoxic Lysosome

Area of Science:

• Biomineralization and Skeletal Development
• Cellular Mechanisms of Bone Remodeling
• Hypoxia and Cellular Responses

Background:

• Osteoclast (OC) roles in mandibular condyle morphogenesis and hypoxic effects on bone remodeling are not fully understood.
• Cathepsin K-positive (ctsk+) OCs are key players in bone resorption and tissue organization.
• Hypoxia-inducible factor-1α (HIF-1α) is crucial for cellular adaptation to low oxygen environments.

Purpose of the Study:

• To investigate the hypoxia response and functions of ctsk+ OCs in condylar tissue organization.
• To elucidate the role of HIF-1α in ctsk+ OC-mediated regulation of mandibular condyle development.
• To identify molecular pathways governing OC function under hypoxic conditions.

Main Methods:

• Genetic ablation of ctsk+ cells using diphtheria toxin receptor (DTR) transgenic mice.
• Conditional knockout of HIF-1α in ctsk+ cells (HIF-1α∆ctsk-cre mice).
• Analysis of mandibular condylar cartilage (MCC) morphology, chondrocyte markers, osteoblastic factors, and bone resorption mediators.

Main Results:

• Genetic ablation of ctsk+ cells led to cartilage accumulation and impaired subchondral bone formation.
• HIF-1α deficiency in ctsk+ OCs initially caused cartilage accumulation but later resulted in cartilage reduction and accelerated mineralization.
• HIF-1α deficiency in OCs disrupted ruffled border structure, lysosomal biogenesis, and identified the TSC2-mTORC1-TFEB pathway.

Conclusions:

• Ctsk+ OCs exhibit a dual role: suppressing chondrocyte proliferation/hypertrophy and regulating osteogenesis.
• HIF-1α signaling in ctsk+ OCs is critical for proper calcified cartilage degradation and lysosomal function.
• Dysregulation of OCs and HIF-1α disrupts the cartilage-to-bone transition in mandibular condyle development.