The retinoic acid-related orphan receptors (RORs) signaling axis in skeletal homeostasis: mechanistic insights and chronotherapeutic prospects.

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-RORα, RORβ, and RORγ-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

RORα/β/γ exhibit distinct ligand-binding architectures that confer subtype-specific transcriptional regulation, enabling coordinated control over osteoblast, osteoclast, and osteocyte activity. Functionally, RORα promotes osteogenesis and supports circadian transcriptional oscillation; RORβ acts as a transcriptional repressor limiting osteoblast differentiation; and RORγt mediates osteoimmune crosstalk via the 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.

CONCLUSIONS

RORα, RORβ, and RORγ 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 RORγt signaling, and optimizing chronopharmacological strategies to enable time-synchronized, subtype-selective interventions.