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