FKBP10 mitigates osteoporosis by restraining the HSPA5-coupled ERS-pyroptosis axis to enhance osteogenic differentiation in BMSCs.

BACKGROUND

Osteoporosis is characterized by progressive bone deterioration and is closely associated with impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Mutations in FK506-binding protein 10 (FKBP10) are linked to osteogenesis imperfecta. However, the role of FKBP10 in osteoporosis and osteogenic differentiation of BMSCs remains unclear.

METHODS

Serum FKBP10 levels were examined in individuals with different bone mineral density. An ovariectomized (OVX) mouse model was established to mimic osteoporosis, and adeno-associated virus serotype 9 (AAV9) was used to achieve FKBP10 overexpression in vivo. Osteoporotic bone phenotypes were assessed by Micro-CT, hematoxylin and eosin staining, and Masson staining. Loss- and gain-of-function experiments were performed in BMSCs using siRNA and overexpression plasmids. Osteogenic differentiation was assessed by alkaline phosphatase staining and Alizarin red S staining. The underlying mechanism was investigated by RNA sequencing, immunofluorescence, co-immunoprecipitation, and protein degradation assays.

RESULTS

FKBP10 levels were reduced in the serum of patients with osteoporosis, as well as in bone tissue and primary BMSCs from OVX mice. AAV9-mediated FKBP10 overexpression attenuated OVX-induced bone loss. FKBP10 knockdown impaired osteogenic differentiation of BMSCs, whereas FKBP10 overexpression enhanced osteogenic differentiation. Mechanistically, FKBP10 knockdown activated Caspase-1-mediated pyroptosis in BMSCs. Further investigation confirmed that FKBP10 directly interacted with heat-shock-protein family A member 5 (HSPA5) and promoted HSPA5 lysosomal degradation, thereby alleviating HSPA5-associated sustained endoplasmic reticulum stress (ERS) and subsequent pyroptosis.

CONCLUSIONS

Our findings identify FKBP10 as a protective regulator that preserves the osteogenic differentiation capacity of BMSCs and attenuates osteoporosis progression by restraining the HSPA5-associated ERS-pyroptosis pathway.