miR-381-3p 通过靶向 KLF5/Wnt/β-连环蛋白信号通路抑制成骨分化从而加重去卵巢诱导的骨质疏松症。
Mir-381-3p aggravates ovariectomy-induced osteoporosis by inhibiting osteogenic differentiation through targeting KLF5/Wnt/β-catenin signaling pathway.
机构信息
Department of Orthopedic surgery, The First Affiliated Hospital of Harbin Medical University, No.23, Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China.
Department of Orthopedic surgery, The Fifth Hospital of Harbin, Harbin, Heilongjiang, 150036, China.
出版信息
J Orthop Surg Res. 2024 Aug 17;19(1):480. doi: 10.1186/s13018-024-04992-6.
BACKGROUND
Increasing evidence shows the pivotal significance of miRNAs in the pathogenesis of osteoporosis. miR-381-3p has been identified as an inhibitor of osteogenesis. This study explored the role and mechanism of miR-381-3p in postmenopausal osteoporosis (PMOP), the most common type of osteoporosis.
METHODS
Bilateral ovariectomy (OVX) rat model was established and miR-381-3p antagomir was administrated through the tail vein in vivo. The pathological changes in rats were assessed through the evaluation of serum bone turnover markers (BALP, PINP, and CTX-1), hematoxylin and eosin (H&E) staining, as well as the expression of osteoblast differentiation biomarkers. Moreover, isolated bone marrow mesenchymal stem cells from OVX-induced rats (OVX-BMMSCs) were utilized to explore the impact of miR-381-3p on osteoblast differentiation. In addition, the target gene and downstream pathway of miR-381-3p were further investigated both in vivo and in vitro.
RESULTS
miR-381-3p expression was elevated, whereas KLF5 was suppressed in OVX rats. miR-381-3p antagomir decreased serum levels of bone turnover markers, improved trabecular separation, promoted osteoblast differentiation biomarker expression in OVX rats. ALP activity and mineralization were suppressed, and levels of osteoblast differentiation biomarkers were impeded after miR-381-3p overexpression during osteoblast differentiation of OVX-BMMSCs. While contrasting results were found after inhibition of miR-381-3p. miR-381-3p targets KLF5, negatively affecting its expression as well as its downstream Wnt/β-catenin pathway, both in vivo and in vitro. Silencing of KLF5 restored Wnt/β-catenin activation induced by miR-381-3p antagomir.
CONCLUSION
miR-381-3p aggravates PMOP by inhibiting osteogenic differentiation through targeting KLF5/Wnt/β-catenin pathway. miR-381-3p appears to be a promising candidate for therapeutic intervention in PMOP.
背景
越来越多的证据表明 miRNAs 在骨质疏松症的发病机制中具有关键意义。miR-381-3p 已被确定为成骨抑制因子。本研究探讨了 miR-381-3p 在绝经后骨质疏松症（PMOP）中的作用和机制，PMOP 是最常见的骨质疏松症类型。
方法
建立双侧卵巢切除（OVX）大鼠模型，体内通过尾静脉给予 miR-381-3p 拮抗剂。通过评估血清骨转换标志物（BALP、PINP 和 CTX-1）、苏木精和伊红（H&E）染色以及成骨分化生物标志物的表达来评估大鼠的病理变化。此外，还利用 OVX 诱导的大鼠分离的骨髓间充质干细胞（OVX-BMMSCs）来探讨 miR-381-3p 对成骨分化的影响。此外，还在体内和体外进一步研究了 miR-381-3p 的靶基因和下游通路。
结果
OVX 大鼠中 miR-381-3p 表达上调，KLF5 表达受抑制。miR-381-3p 拮抗剂降低了 OVX 大鼠血清骨转换标志物水平，改善了骨小梁分离，促进了 OVX 大鼠成骨分化生物标志物的表达。OVX-BMMSCs 成骨分化时，miR-381-3p 过表达抑制 ALP 活性和矿化，阻碍成骨分化生物标志物的表达。而抑制 miR-381-3p 则得到相反的结果。miR-381-3p 靶向 KLF5，负调控其表达及其下游 Wnt/β-catenin 通路，在体内和体外均如此。沉默 KLF5 恢复了 miR-381-3p 拮抗剂诱导的 Wnt/β-catenin 激活。
结论
miR-381-3p 通过靶向 KLF5/Wnt/β-catenin 通路抑制成骨分化，加重 PMOP。miR-381-3p 似乎是 PMOP 治疗干预的有前途的候选物。
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