BACKGROUND: The global rise in aging populations has substantially increased the clinical and socioeconomic burden of osteoporosis (OP), a disorder characterized by impaired bone formation and excessive resorption. Disruption of circadian rhythmicity is increasingly recognized as a significant contributor to skeletal fragility and fracture risk. The retinoic acid-related orphan receptor (ROR) family-RORĪ±, RORĪ², and RORĪ³-integrates circadian regulation with immune and metabolic pathways essential to bone remodeling, presenting emerging therapeutic opportunities.
METHODS: We systematically synthesized current evidence spanning four major dimensions of ROR biology relevant to skeletal physiology: (1) structural characteristics and ligand specificity, (2) subtype-dependent roles in bone homeostasis, (3) molecular and cellular regulatory mechanisms, and (4) translational progress and therapeutic potential, including chronopharmacological strategies.
RESULTS: RORĪ±/Ī²/Ī³ exhibit distinct ligand-binding architectures that confer subtype-specific transcriptional regulation, enabling coordinated control over osteoblast, osteoclast, and osteocyte activity. Functionally, RORĪ± promotes osteogenesis and supports circadian transcriptional oscillation; RORĪ² acts as a transcriptional repressor limiting osteoblast differentiation; and RORĪ³t mediates osteoimmune crosstalkthe IL-17 axis to modulate osteoclastogenesis. Preclinical studies demonstrate promising efficacy of ROR-directed agents-including agonists, inverse agonists, and isoform-selective inhibitors-and highlight the importance of circadian-aligned therapeutic administration. via
CONCLUSIONS: RORĪ±, RORĪ², and RORĪ³ function as complementary regulators of bone homeostasis and represent compelling targets for precision therapeutics against OP and related skeletal disorders. Future research should prioritize defining spatiotemporal regulation within bone microenvironments, quantifying immune-mediated RORĪ³t signaling, and optimizing chronopharmacological strategies to enable time-synchronized, subtype-selective interventions.
