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Targeting NAMPT-OPA1 for treatment of senile osteoporosis
Chao-Wen Bai1, Bo Tian1, Ming-Chao Zhang1
1Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Abstract:
Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age-related bone loss. Overexpression of Nampt ameliorates the senescence-associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT-OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP.
Insights
Nicotinamide phosphoribosyltransferase (NAMPT) regulates bone marrow mesenchymal stem cell (BMSC) senescence and bone formation. Activating NAMPT with P7C3 prevents age-related bone loss and senile osteoporosis by improving mitochondrial function.
Area of Science:
- Cell Biology
- Gerontology
- Biochemistry
Background:
- Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs stemness and osteogenic differentiation, leading to senile osteoporosis (SOP).
- Nicotinamide phosphoribosyltransferase (NAMPT) homeostasis is implicated in aging and disease, with its role in BMSCs and SOP not fully elucidated.
Purpose of the Study:
- To investigate the role of NAMPT in BMSC senescence and osteogenic differentiation.
- To explore the therapeutic potential of NAMPT activation for senile osteoporosis.
Main Methods:
- Assessed NAMPT levels and osteogenic differentiation in BMSCs from aged humans and mice.
- Utilized gene knockdown and overexpression of Nampt in BMSCs.
- Investigated the effect of P7C3, a NAMPT activator, on aged BMSCs and SOP models.
- Examined mitochondrial dynamics and the NAMPT-OPA1 signaling axis.
Main Results:
- Reduced NAMPT levels and impaired osteogenesis were observed in aged BMSCs.
- Nampt knockdown promoted lipogenic differentiation and exacerbated bone loss, while Nampt overexpression ameliorated senescence and enhanced osteogenesis.
- NAMPT inhibited BMSC senescence by enhancing OPA1 expression, crucial for mitochondrial fusion and function.
- P7C3 treatment prevented BMSC senescence and reduced SOP bone loss by improving mitochondrial function via the NAMPT-OPA1 pathway.
Conclusions:
- NAMPT is a key regulator of BMSC senescence and osteogenic differentiation.
- P7C3 represents a novel therapeutic strategy for preventing and treating senile osteoporosis by targeting the NAMPT-OPA1 signaling axis.
