Kunming Medical University

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.

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.

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.

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.

Thirteen previously undescribed sesquiterpenoids, named magnorins A-M (1-13), were isolated from the fruits of Magnolia grandiflora Linn., along with five known analogues. The structures and absolute configurations of 1-13 were characterized using HR-ESI-MS, 1D and 2D NMR spectroscopy, X-ray crystallography, and by comparing experimental electronic circular dichroism data with theoretical calculations. Notably, compound 1 was a unique sesquiterpenoid with a bicyclo[5.3.1]undecane framework, derived from germacrane through the connection of C-5 and C-14. Compounds 2 and 3 were uncommon C₁₇ homogermacrane-type sesquiterpenoid lactones, while 8 was the first germacrane-type sesquiterpenoid containing an oxetane ring bridging C-7 and C-11. A plausible biosynthetic pathway for 1 was also postulated. The cytotoxic effects of all sesquiterpenoids were assessed by measuring their ability to inhibit the growth of A549, MDA-MB-231, and SW480 cancer cells. Compounds 15-18 exhibited prominent cytotoxic activity, with IC₅₀ values ranging from 3.70 to 20.28 μM, compared to the control group.

Small extracellular vesicles (sEVs) show therapeutic potential for periodontitis but functional components remain unclear, limiting clinical periodontal therapy application. Identifying key bioactive molecules and enhancing their functions via engineering strategies may overcome these limitations. By comparing the periodontal tropism of sEVs from different stem cells and conducting functional miRNA profiling, we identified miR-423-5p as a key component for periodontal ligament cell (PDLC) osteogenic differentiation by targeting PLCB1 (Phospholipase C Beta 1). We engineered miR-423-5p-enriched sEVs (sEVs^miR-423-5p) with miRNA loading levels up to 100,000-fold higher than those of native sEVs. Compared with unmodified sEVs, sEVs^miR-423-5p promoted the formation of Sfrp2⁺ osteogenic fibroblasts at periodontal defect sites, ultimately facilitating early osteogenesis and regeneration of a native-like cementum-PDL-alveolar bone complex. These findings establish miR-423-5p as a pivotal osteoinductive effector in sEVs and demonstrate that its targeted enrichment markedly amplifies the regenerative capacity of sEVs, laying the groundwork for personalized nanovesicle-based regenerative therapies.