PINK1 deficiency exacerbates age-related bone loss in association with enhanced inflammatory adipocyte differentiation
Abstract
Age-related bone loss contributes to frailty, fractures, and increased mortality in the elderly, yet current osteoporosis treatments have limited long-term efficacy. Mitochondrial dysfunction is a hallmark of skeletal aging, but its role in mesenchymal lineage commitment remains unclear. Here, we investigated PTEN-induced kinase 1 (PINK1), a serine/threonine kinase essential for mitophagy, in regulating bone mass and adipogenic differentiation during aging. Using Pink1 knockout (Pink1 -/-) mice, we found that Pink1 deficiency exacerbated trabecular bone loss and promoted adipocyte hypertrophy in white adipose tissue. Calvarial pre-osteoblasts from Pink1 -/- mice displayed impaired osteogenic differentiation and increased adipogenesis, evidenced by reduced alkaline phosphatase (ALP) activity, mineralization, and osteogenic gene expression, alongside elevated lipid accumulation. In vitro, siRNA-mediated Pink1 knockdown in 3T3-L1 cells triggered adipogenic, inflammatory, and oxidative stress responses, while suppressing mitochondrial function and respiration. Collectively, these findings reveal that PINK1 preserves skeletal integrity by maintaining mitochondrial homeostasis and restraining stress-induced adipogenic reprogramming. Our study identifies the PINK1-mitophagy axis as a potential therapeutic target for preventing age-related bone loss and preserving bone health.
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