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Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox

Wang Zhen-Xing,Luo Zhong-Wei,Li Fu-Xing-Zi,Cao Jia,Rao Shan-Shan,Liu Yi-Wei,Wang Yi-Yi,Zhu Guo-Qiang,Gong Jiang-Shan,Zou Jing-Tao,Wang Qiang,Tan Yi-Juan,Zhang Yan,Hu Yin,Li You-You,Yin Hao,Wang Xiao-Kai,He Ze-Hui,Ren Lu,Liu Zheng-Zhao,Hu Xiong-Ke,Yuan Ling-Qing,Xu Ran,Chen Chun-Yuan,Xie Hui

Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called “calcification paradox”. Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.