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

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.

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.

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.

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.

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.