Department of Pain, Changchun University of Traditional Chinese Medicine Affiliated Hospital, Changchun, China.
J Tissue Eng Regen Med. 2022 Mar;16(3):311-329. doi: 10.1002/term.3279. Epub 2022 Jan 11.
Osteoporosis is defined as a skeletal disorder characterized by impairment in bone strength. The potential application of lncRNAs as therapeutic targets for osteoporosis has been unveiled. This study investigated the regulatory mechanism of lncRNA MALAT1 in the differentiation of bone marrow stem cells (BMSCs) and macrophages (Mø) in osteoporosis. MALAT1 expression in peripheral blood of elderly osteoporosis patients and healthy volunteers was detected. BMSCs and mononuclear Mø were isolated and cultured. Osteogenic differentiation of BMSCs and osteoclastic differentiation of Mø were induced. BMSCs and Mø were transfected with si-MALAT1, miR-124-3p mimics, miR-124-3p inhibitor, or pcDNA IGF2BP1, followed by detection of cell differentiation. The target microRNAs (miRs) and downstream genes and signaling pathways of MALAT1 were examined. The ovariectomy-induced mouse model of osteoporosis was established, and the mice were injected with pcDNA-MALAT1. MALAT1 was downregulated in osteoporosis patients, increased in BMSCs after osteogenic differentiation, and diminished in Mø after osteoclastic differentiation. Downregulation of MALAT1 repressed osteogenic differentiation of BMSCs and facilitated osteoclastic differentiation of Mø. MALAT1 upregulated IGF2BP1 expression by competitively binding to miR-124-3p. miR-124-3p silencing reversed the effect of si-MALAT1 on BMSCs and Mø differentiation, and IGF2BP1 upregulation averted the effect of overexpressed-miR-124-3p by activating the Wnt/β-catenin pathway. Upregulation of MALAT1 activated the Wnt/β-catenin pathway and attenuated bone injury in mice. In conclusion, lncRNA MALAT1 promoted the osteogenic differentiation of BMSCs and inhibited osteoclastic differentiation of Mø in osteoporosis via the miR-124-3p/IGF2BP1/Wnt/β-catenin axis.
骨质疏松症定义为一种以骨强度受损为特征的骨骼疾病。长链非编码 RNA (lncRNA) 作为骨质疏松症治疗靶点的潜在应用已经被揭示。本研究探讨了 lncRNA MALAT1 在骨质疏松症骨髓间充质干细胞 (BMSCs) 和巨噬细胞 (Mø) 分化中的调控机制。检测老年骨质疏松症患者和健康志愿者外周血 MALAT1 的表达。分离培养 BMSCs 和单核 Mø。诱导 BMSCs 成骨分化和 Mø 破骨分化。用 si-MALAT1、miR-124-3p 模拟物、miR-124-3p 抑制剂或 pcDNA IGF2BP1 转染 BMSCs 和 Mø，然后检测细胞分化。检测 MALAT1 的靶 microRNAs (miRs) 和下游基因及信号通路。建立去卵巢诱导的骨质疏松症小鼠模型，向小鼠注射 pcDNA-MALAT1。骨质疏松症患者 MALAT1 下调，成骨分化后 BMSCs 中 MALAT1 增加，破骨分化后 Mø 中 MALAT1 减少。下调 MALAT1 抑制 BMSCs 成骨分化，促进 Mø 破骨分化。MALAT1 通过竞争性结合 miR-124-3p 上调 IGF2BP1 表达。miR-124-3p 沉默逆转了 si-MALAT1 对 BMSCs 和 Mø 分化的影响，IGF2BP1 上调通过激活 Wnt/β-catenin 通路逆转了过表达 miR-124-3p 的作用。上调 MALAT1 激活 Wnt/β-catenin 通路，减轻小鼠骨损伤。总之，lncRNA MALAT1 通过 miR-124-3p/IGF2BP1/Wnt/β-catenin 轴促进骨质疏松症 BMSCs 成骨分化，抑制 Mø 破骨分化。
