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首页> 外文期刊>Cellular Physiology and Biochemistry >Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells
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Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells

机译：Wnt5a / FZD4介导骨骼间充质干细胞的机械拉伸诱导成骨分化。

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Background/Aims Mechanical stimulation and WNT signalling have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding the regulation of WNT signalling molecule expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. Methods Microarrays of BMSCs from elderly individuals or patients with osteoporosis (GSE35959) from the GEO database were analysed using GeneSight-Lite 4.1.6 (BioDiscovery) and C2 curated gene sets downloaded from Molecular Signatures Database (MSigDB). Realtime PCR and western blotting were used to measure the expression of the indicated genes. ALP and Alizarin red staining were used to evaluate the osteogenesis of BMSCs. Results In this study, we investigated whether mechanical loading directly regulates the expression of WNT signalling molecules and examined the role of WNT signalling in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found downregulation of the GPCR ligand binding gene set in the BMSCs of patients with osteoporosis. Then, we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. FZD4 was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, and the JNK signalling pathway was activated. FZD4 knockdown inhibited the mechanical stimuli-induced osteogenesis and JNK activity. More importantly, we found an activating effect of WNT5A and FZD4 that regulated bone formation in response to hindlimb unloading in mice, and pretreatment with WNT5A or activation of the expression of FZD4 partly rescued the osteoporosis caused by mechanical unloading. Conclusions Our results demonstrate, for the first time, that mechanical stimulation alters the expression of genes involved in the osteogenic differentiation of BMSCs via the direct regulation of FZD4 and that therapeutic WNT5A and FZD saRNA may be an efficient strategy for enhancing bone formation under mechanical stimulation.
机译：背景/目的机械刺激和WNT信号传导在调节骨髓基质细胞（BMSCs）的成骨分化和骨形成中起重要作用。然而，关于WNT信号分子表达的调节以及因此在成骨过程中BMSC的成骨分化的了解还很少。方法使用GeneSight-Lite 4.1.6（BioDiscovery）和从分子特征数据库（MSigDB）下载的C2精选基因集，分析来自GEO数据库的老年人或骨质疏松患者（BSE）的BMSC的微阵列。使用实时PCR和蛋白质印迹法测量指示基因的表达。 ALP和茜素红染色用于评估BMSC的成骨性。结果在这项研究中，我们调查了机械负荷是否直接调节WNT信号分子的表达，并研究了WNT信号在机械负荷触发的成骨分化和骨形成中的作用。我们首先研究了骨质疏松症患者样品的微阵列，发现骨质疏松症患者BMSC中GPCR配体结合基因集的下调。然后，我们证明了机械刺激可以在体内和体外调节成骨和骨形成。 FZD4在周期机械拉伸（CMS）诱导的成骨分化过程中被上调，并且JNK信号通路被激活。 FZD4组合式抑制了机械刺激诱导的成骨和JNK活性。更重要的是，我们发现WNT5A和FZD4的激活效应调节了小鼠响应后肢卸载的骨形成，而用WNT5A预处理或激活FZD4的表达部分挽救了机械卸载引起的骨质疏松。结论我们的结果首次证明了机械刺激通过直接调节FZD4改变了BMSCs成骨分化相关基因的表达，并且治疗性WNT5A和FZD saRNA可能是在机械刺激下增强骨形成的有效策略。 。

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