Osteocytic Pink1/Prkn modulates M6P metabolism and contributes to GC-induced bone loss.

BACKGROUND

Glucocorticoid-induced osteoporosis (GIOP) is largely driven by osteocyte dysfunction, which disrupts the balance between bone formation and bone resorption. The Pink1/Prkn-mediated mitophagy pathway plays a crucial role in maintaining mitochondrial and metabolic homeostasis in osteocytes; however, its involvement in GIOP remains unclear.

METHODS

Osteocyte-specific Pink1 and Prkn conditional knockout mice (Dmp1 cre Pink1 fl/fl and Dmp1 cre Prkn fl/fl ) were generated to investigate the role of osteocytic Pink1/Prkn in bone homeostasis under glucocorticoid (GC) exposure. Micro-computed tomography, histological analyses, transcriptomic and metabolomic profiling, and osteocyte-osteoblast/osteoclast co-culture assays were performed to evaluate skeletal phenotypes and metabolic alterations.

RESULTS

Deletion of Pink1 or Prkn in osteocytes did not affect bone mass under basal conditions but significantly aggravated GC-induced bone loss. Osteocytic Pink1/Prkn deficiency was associated with enhanced osteoclast activation and impaired osteoblast function. Integrated transcriptomic and metabolomic analyses indicated marked alterations in glycolytic and mannose-related metabolism, including a consistent reduction in mannose-6-phosphate (M6P) accompanied by reduced expression of its key biosynthetic enzyme, phosphomannose isomerase (MPI). Functionally, supplementation with exogenous M6P restored the osteoclast-osteoblast balance in Pink1/Prkn-deficient osteocytes in vitro. In vivo, D-mannose supplementation alleviated GC-induced bone loss in both osteocytic Pink1/Prkn knockout and wild-type mice.

CONCLUSION

These findings identify a previously unrecognized potential Pink1/Prkn-MPI-M6P metabolic axis that can contribute to osteocyte function under GC stress and highlight mannose/M6P metabolism as a potential therapeutic target for glucocorticoid-induced osteoporosis.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study identifies a previously unrecognized Pink1/Prkn-MPI-M6P metabolic axis in osteocytes that protects against glucocorticoid-induced bone loss. By linking mitochondrial quality control to mannose metabolism and osteocyte-mediated regulation of bone remodeling, our findings provide mechanistic insight into the pathogenesis of glucocorticoid-induced osteoporosis. Importantly, the observation that D-mannose supplementation alleviates bone loss suggests that targeting mannose/M6P metabolism may represent a novel therapeutic strategy for preventing or treating GIOP.