Department of Orthopedics, Minhang Hospital, Fudan University, 170 Xin Song Road, Shanghai 201199, PR China.
Department of Biochemistry and Molecular Biology, School of medicine, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
Bone. 2020 Aug;137:115444. doi: 10.1016/j.bone.2020.115444. Epub 2020 May 21.
Osteoporosis (OP) is a systemic skeletal disorder with the characteristics of bone mass reduction and microarchitecture deterioration, resulting in bone fragility and increased fracture risk. A reduction in the osteoblast-differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered as a basic pathogenesis of osteoporosis. miRNAs play a substantial role in the development and differentiation of BMSCs. In the present study, we found that miR-1-3p was significantly downregulated in the bones of Chinese osteoporotic patients (n = 29). Secreted frizzled-related protein 1 (SFRP1) was predicted as a target gene of miR-1-3p via the TargetScan and PicTar softwares and validated by dual-luciferase reporter assays. The findings revealed that the expression of SFRP1 was inversely correlated with miR-1-3p in osteoporotic patients. We induced mouse MSCs (mMSCs) to osteogenesis or adipogenesis and found that miR-1-3p was upregulated during osteogenesis but downregulated during adipogenesis. The overexpression of miR-1-3p stimulated osteogenesis and inhibited adipogenesis of mMSCs. In addition, ovariectomized (OVX) mice were tested and the function of miR-1-3p in vivo was explored. Immunohistochemistry and histomorphometric assays showed that in vivo inhibition of miR-1-3p increased the expression level of SFRP1 and reduced bone formation and bone mass. Furthermore, tartrate-resistant acid phosphatase (TRAP) staining indicated that the in vivo suppression of miR-1-3p promoted osteoclast activity, suggesting that miR-1-3p may influence bone mass by regulating bone resorption. It can be concluded that miR-1-3p plays a pivotal role in the pathogenesis of osteoporosis via targeting SFRP1 and may be a potential therapeutic target for osteoporosis.
骨质疏松症（OP）是一种以骨量减少和微观结构恶化为特征的全身性骨骼疾病，导致骨骼脆弱和骨折风险增加。骨髓间充质干细胞（BMSCs）成骨分化减少被认为是骨质疏松症的基本发病机制。miRNAs 在 BMSCs 的发育和分化中发挥重要作用。在本研究中，我们发现 miR-1-3p 在 29 例中国骨质疏松症患者的骨骼中显著下调。靶向预测软件 TargetScan 和 PicTar 预测 SFRP1 是 miR-1-3p 的靶基因，并通过双荧光素酶报告基因实验验证。结果表明，SFRP1 的表达与骨质疏松症患者的 miR-1-3p 呈负相关。我们诱导小鼠间充质干细胞（mMSCs）成骨或成脂分化，发现 miR-1-3p 在成骨过程中上调，而在成脂过程中下调。miR-1-3p 的过表达刺激 mMSCs 成骨并抑制其成脂分化。此外，我们还检测了去卵巢（OVX）小鼠，并探索了 miR-1-3p 在体内的功能。免疫组化和组织形态计量学分析表明，体内抑制 miR-1-3p 增加了 SFRP1 的表达水平，减少了骨形成和骨量。此外，抗酒石酸酸性磷酸酶（TRAP）染色表明，体内抑制 miR-1-3p 促进了破骨细胞的活性，表明 miR-1-3p 可能通过调节骨吸收来影响骨量。综上所述，miR-1-3p 通过靶向 SFRP1 在骨质疏松症发病机制中发挥关键作用，可能是骨质疏松症的潜在治疗靶点。
