Department of Orthopedics, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
Department of Teaching and Research, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
J Cell Mol Med. 2021 Feb;25(4):2069-2081. doi: 10.1111/jcmm.16139. Epub 2021 Jan 12.
Osteoporosis is a metabolic disease that results from oxidative stress or inflammation in renal disorders. microRNAs (miRNAs) are recently implicated to participate in osteoporosis, but the mechanism remains largely unexplored. Herein, we aimed to explore the potential role of miR-15b in osteoblast differentiation and autophagy in osteoporosis. We established osteoporosis models through ovariectomy and determined that miR-15b was highly expressed whereas USP7 and KDM6B were poorly expressed in tissue of osteoporosis mice. Treatment of silenced miR-15b resulted in the elevation of decreased bone mineral density (BMD), the maximum elastic stress and the maximum load of osteoporosis mice. In osteoblasts, miR-15 overexpression decreased proliferation but suppressed the cell differentiation and autophagy, accompanied with decreased expression of USP7. Mechanistically, miR-15 bound and inhibited USP7 expression, while overexpression of USP7 promoted autophagy of osteoblasts. USP7, importantly, strengthened the stability of KDM6B and promoted KDM6B expression. MG132 protease inhibitor increased KDM6B and USP7 expression in osteoblasts. Silencing of KDM6B reversed the promoting effect on autophagy and proliferation induced by overexpression of USP7. Taken altogether, miR-15b inhibits osteoblast differentiation and autophagy to aggravate osteoporosis by targeting USP7 to regulate KDM6B expression.
骨质疏松症是一种代谢疾病，由肾脏疾病中的氧化应激或炎症引起。 microRNAs（miRNAs）最近被认为参与了骨质疏松症，但机制仍在很大程度上未被探索。在此，我们旨在探索 miR-15b 在成骨细胞分化和骨质疏松症自噬中的潜在作用。我们通过卵巢切除术建立了骨质疏松症模型，并确定 miR-15b 在骨质疏松症小鼠组织中高表达，而 USP7 和 KDM6B 表达水平较低。沉默 miR-15b 的治疗导致骨质疏松症小鼠的骨矿物质密度（BMD）、最大弹性应力和最大载荷降低。在成骨细胞中，miR-15 过表达会降低增殖能力，但会抑制细胞分化和自噬，同时 USP7 的表达也会降低。机制上，miR-15 结合并抑制 USP7 的表达，而 USP7 的过表达促进了成骨细胞的自噬。重要的是，USP7 增强了 KDM6B 的稳定性并促进了 KDM6B 的表达。MG132 蛋白酶抑制剂增加了成骨细胞中 KDM6B 和 USP7 的表达。沉默 KDM6B 逆转了 USP7 过表达对自噬和增殖的促进作用。总的来说，miR-15b 通过靶向 USP7 调节 KDM6B 的表达，抑制成骨细胞分化和自噬，从而加重骨质疏松症。
