Functional matrix vesicle replacement partially restores chemo-mechanical coupling in the aged bone niche.
basic_science · Level V
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- Record sourced from PubMed, PMID 42462727.
- Also identified by DOI 10.1016/j.xcrm.2026.102923.
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Abstract
Skeletal aging involves pyrophosphate/phosphate disequilibrium and impaired mechanotransduction, which together constrain osteogenic repair. We develop OsteoVes, a matrix-vesicle-mimetic extracellular organelle that combines tissue-nonspecific alkaline phosphatase (ALP)-mediated inorganic pyrophosphate (PPi) hydrolysis, nano-hydroxyapatite nucleation, and a mesenchymal stem cell-derived membrane interface for extracellular matrix anchoring. In aged human mesenchymal stem/stromal cells (MSCs), OsteoVes restores the Pi/PPi set point, suppresses PPARG activity, promotes RUNX2 nuclear translocation, and supports osteogenic differentiation. OsteoVes also increases actomyosin tension and engages an ITG/FAK-PIEZO1-JNK/c-JUN-RUNX2 mechanotransduction-associated pathway. In elderly osteopenic/osteoporotic patient-derived MSCs, OsteoVes supports ALP activity and matrix mineralization. Systemic administration improves trabecular microarchitecture and mechanical properties in naturally aged mice within 4 weeks, remains active in Alpl<sup>+/-</sup> progeroid mice, and elicits osteoanabolic serum and imaging responses without evident short-term toxicity in metabolically aged rhesus macaques. These findings identify matrix vesicle (MV) dysfunction as an extracellular osteometabolic control point for short-term chemo-mechanical rescue.