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

• Published in: Nature communications Vol. 13; no. 1; p. 1453
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 49/61; 64/110; 64/60; 692/163/2743/316/801; 692/4019/592/2193; 692/698/1671/63; Adipogenesis; Adipose tissue; Aging; Alendronic acid; Animals; Biomedical materials; Bisphosphonates; Bone marrow; Bone Matrix; Bone resorption; Calcification; Calcification (ectopic); Cell Differentiation; Extracellular Vesicles; Female; Humanities and Social Sciences; Intravenous administration; Matrix vesicles; Menopause; Mesenchymal Stem Cells; Mesenchyme; Mice; MicroRNAs - genetics; multidisciplinary; Muscles; Oophorectomy; Osteoblastogenesis; Osteogenesis; Osteoporosis; Ovariectomy; Paradoxes; Science; Science (multidisciplinary); Smooth muscle; Stromal cells; Vesicles; Vitamin D3
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29191-x

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. This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.