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Nicotinamide Mononucleotide Alleviates Osteoblast Senescence Induction and Promotes Bone Healing in Osteoporotic Mice
ZuFu Lu1,2, Liting Jiang3,4, Pooria Lesani1,2
1Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, the University of Sydney, Sydney, New South Wales, Australia.
Abstract:
Combating the accumulated senescent cells and the healing of osteoporotic bone fractures in the older remains a significant challenge. Nicotinamide mononucleotide (NMN), a precursor of NAD+, is an excellent candidate for mitigating aging-related disorders. However, it is unknown if NMN can alleviate senescent cell induction and enhance osteoporotic bone fracture healing. Here we show that NMN treatment partially reverses the effects of tumor necrosis factor-alpha (TNF-α) on human primary osteoblasts (HOBs): senescent cell induction, diminished osteogenic differentiation ability, and intracellular NAD+ and NADH levels. Mechanistically, NMN restores the mitochondrial dysfunction in HOBs induced by TNF-α evidenced by increased mitochondrial membrane potential and reduced reactive oxidative species and mitochondrial mass. NMN also increases mitophagy activity by down-regulating P62 expression and up-regulating light chain 3B-II protein expression. In addition, the cell senescence protective effects of NMN on HOBs are mitigated by a mitophagy inhibitor (Bafilomycin A1). In vivo, NMN supplementation attenuates senescent cell induction in growth plates, partially prevents osteoporosis in an ovariectomized mouse model, and accelerates bone healing in osteoporotic mice. We conclude that NMN can be a novel and promising therapeutic candidate to enhance bone fracture healing capacity in the older.
Insights
Nicotinamide mononucleotide (NMN) helps combat senescent cells and improves bone fracture healing in older individuals. This study shows NMN restores mitochondrial function and enhances mitophagy, offering a promising therapeutic approach for age-related bone conditions.
Area of Science:
- Gerontology
- Biomedical Engineering
- Cell Biology
Background:
- Accumulated senescent cells and impaired bone fracture healing are significant challenges in aging populations.
- Nicotinamide mononucleotide (NMN), an NAD+ precursor, shows potential for mitigating age-related disorders.
- The efficacy of NMN in addressing senescent cell induction and osteoporotic bone fracture healing remains unexplored.
Purpose of the Study:
- To investigate the effects of NMN on senescent cell induction and osteogenic differentiation in human primary osteoblasts (HOBs) exposed to tumor necrosis factor-alpha (TNF-α).
- To elucidate the underlying mechanisms of NMN's action, focusing on mitochondrial function and mitophagy.
- To evaluate the in vivo efficacy of NMN in preventing osteoporosis and accelerating bone healing in aged and osteoporotic mouse models.
Main Methods:
- Treatment of TNF-α-induced senescent HOBs with NMN.
- Assessment of mitochondrial function (membrane potential, reactive oxygen species, mitochondrial mass).
- Analysis of mitophagy markers (P62, light chain 3B-II) and use of mitophagy inhibitor (Bafilomycin A1).
- In vivo studies using ovariectomized mice and osteoporotic bone fracture models with NMN supplementation.
Main Results:
- NMN partially reversed TNF-α-induced senescence, restored NAD+/NADH levels, and improved osteogenic differentiation in HOBs.
- NMN normalized mitochondrial dysfunction by increasing membrane potential and reducing reactive oxygen species and mitochondrial mass.
- NMN enhanced mitophagy, evidenced by decreased P62 and increased LC3B-II, an effect blunted by mitophagy inhibition.
- In vivo, NMN attenuated senescence, partially prevented osteoporosis, and accelerated bone healing in osteoporotic mice.
Conclusions:
- NMN effectively mitigates TNF-α-induced cellular senescence and mitochondrial dysfunction in osteoblasts.
- NMN promotes mitophagy, contributing to its senolytic and osteogenic benefits.
- NMN demonstrates therapeutic potential for enhancing bone fracture healing and combating osteoporosis in aging individuals.
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