Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by GNAS gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone. Although impaired osteogenesis of BMSCs is central to FD pathogenesis, the underlying mechanism remains largely elusive. Here we demonstrate that hyperactivation of the cAMP-PRKA/PKA signaling axis disrupts mitochondrial homeostasis through impaired mitophagy, ultimately leading to diminished amorphous calcium phosphate (ACP) secretion and consequent mineralization failure in FD. Mechanistically, in FD BMSCs, PRKA activation inhibits DNM1L/DRP1 recruitment to mitochondria through phosphorylation at S637, thereby suppressing mitochondrial fission. Consequently, excessive mitochondrial fusion leads to an elevated mitochondrial membrane potential, impaired mitophagy, and diminished ACP release. Collectively, our findings reveal a novel signaling nexus linking cAMP-PRKA signaling, mitochondrial dynamics, and biomineralization processes in FD pathogenesis, providing critical insights into the molecular basis of this disorder.
Ling et al. (Mon,) studied this question.