M1 polarization accelerated bone aging through inflammatory signaling transduction regulated by cells crosstalk.
Aging induced chronic inflammation deteriorated bone loss in elderly population. This study aimed to investigate the underling mechanism of bone-immune crosstalk with aging. In clinical, we identified novel inflammatory markers as predictors for osteoporosis in old people, indicating a close relationship between immune system and bone strength. In animal study, more pro-inflammatory macrophages (M1) was identified in aged bone, suggesting a possible mechanism sheered by the altered bone-inmmune interplay. Transcriptomic analyses on senescent bone marrow mesenchymal stem cells (MSCs) suggested that immune signaling and osteoclasts differentiation were involved in MSCs aging. Moreover, single-cell sequencing data analyses (GSE145477) screened 4 co-deferentially expressed genes in this bone-immune system with aging. They were TREM2, TYROBP (encodes DAP12), SYK, and PIK3CD. Then, we established cells co-culture system and verified the age-reduced TREM2 accompanied with DAP12-SYK inactivation, leading to more M1 polarization. Conditioned medium experiments results were consistent with these changes. Pharmacological activation of TREM2-DAP12-SYK axis by a small molecule compound, ADAM10 inhibitor, recovered the macrophages aging and decreased their pro-inflammatory polarization. Therefore, we speculated that the increased M1 polarization by aging-reduced TREM2-DAP12-SYK signaling might be responsible for inflammatory micro-environment in bone tissue. Together, this study elaborated the bone-immune crosstalk with aging through the inflammatory signaling alteration and provided new treatment targets for senile osteoporosis.