Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
Zhen‐Xing Wang, Zhong‐Wei Luo, Fu‐Xing‐Zi Li, Jia Cao, Shan‐Shan Rao, Yi-Wei Liu, Yiyi Wang, Guo‐Qiang Zhu, Jiang-Shan Gong, Jingtao Zou, Qiang Wang, Yi‐Juan Tan, Yan Zhang, Yin Hu, Youyou Li, Hao Yin, Xiaokai Wang, Zehui He, Lu Ren, Zhengzhao Liu, Xiong‐Ke Hu, Ling‐Qing Yuan, Ran Xu, Chun‐Yuan Chen, Hui Xie
Abstract
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.