Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Nat Commun. 2022 Mar 18;13(1):1453. 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.
骨髓间充质干细胞（BMSCs）的脂肪细胞分化而非成骨作用导致与年龄和绝经相关的骨髓脂肪增多和骨质疏松症。血管钙化常与骨质疏松症同时发生，这种矛盾的关联被称为“钙化悖论”。在这里，我们表明，在骨吸收过程中源自衰老骨基质的细胞外囊泡（AB-EVs）促进 BMSC 脂肪生成而不是成骨作用，并增强血管平滑肌细胞的钙化。AB-EVs 的静脉内或髓内注射促进年轻或老年小鼠的骨脂肪失衡，并加重维生素 D3（VD3）诱导的血管钙化。骨吸收抑制剂阿伦膦酸盐（ALE）下调 AB-EVs 的释放并减轻衰老和卵巢切除引起的骨脂肪失衡。在 VD3 处理的老年小鼠中，ALE 抑制卵巢切除引起的血管钙化加重。miR-483-5p 和 miR-2861 在 AB-EVs 中富集，对于 AB-EVs 诱导的骨脂肪失衡和血管钙化的加重是必需的。我们的研究揭示了 AB-EVs 通过转移 miR-483-5p 和 miR-2861 作为钙化悖论的信使的作用。
