Vlashi Rexhina, Zhang Xingen, Wu Mengrui, Chen Guiqian
College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, China.
Department of Orthopedics, Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics & Skeletal Regenerative Medicine, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang 314001, China.
Genes Dis. 2022 Aug 6;10(4):1291-1317. doi: 10.1016/j.gendis.2022.07.011. eCollection 2023 Jul.
Wnt signaling executes an indispensable performance in osteoblast differentiation, bone development, homeostasis, and remodeling. Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of β-catenin in the bone environment. Going through the novel discoveries done via high-throughput sequencing technologies on genetic mouse models, we highlighted the significant contribution of Wnt ligands, co-receptors, inhibitors, their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings. Moreover, the crosstalk between Wnt signaling pathway and BMP, TGF-β, FGF, Hippo, Hedgehog, Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast differentiation and bone development. We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis, glutamine catabolism, and fatty acid oxidation in osteoblast-lineage cells that display an important regulatory arbor in the cellular bioenergetics of the bone. Throughout this evaluation, most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings, are formulated with an aspiration to holistically revamp the present clinical applications involving various monoclonal antibodies therapies that lack specificity, efficacy, and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations. Conclusively, our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening researchers with the possibility to further integrate the identified target molecules into therapeutic strategies for skeletal disorders treatment in the clinic.
Wnt信号在成骨细胞分化、骨骼发育、稳态和重塑过程中发挥着不可或缺的作用。Wnt信号触发细胞内Wnt信号级联反应，从而开始调节β-连环蛋白在骨环境中的作用。通过对基因小鼠模型进行高通量测序技术所取得的新发现，我们强调了Wnt配体、共受体、抑制剂及其在小鼠模型中的相关骨骼表型以及在人类临床中观察到的类似骨病的重要贡献。此外，Wnt信号通路与骨形态发生蛋白（BMP）、转化生长因子-β（TGF-β）、成纤维细胞生长因子（FGF）、河马（Hippo）、刺猬索尼克（Hedgehog）、Notch和血小板衍生生长因子（PDGF）信号通路之间的相互作用被充分证明是协调成骨细胞分化和骨骼发育的潜在基因调控网络。我们还反思了Wnt信号转导在成骨细胞谱系细胞中通过刺激糖酵解、谷氨酰胺分解代谢和脂肪酸氧化来重组细胞代谢的意义，这些细胞代谢在骨细胞生物能量学中显示出重要的调节分支。在整个评估过程中，迄今为止，针对人类骨质疏松症和其他骨病的大多数治疗方法，都旨在全面改进目前涉及各种单克隆抗体疗法的临床应用，这些疗法缺乏特异性、疗效和安全性，转而采用更符合进一步临床考量所需的、满足这三个要求的先进疗法。总之，我们的综述提供了与Wnt信号级联在骨骼系统中的基本意义以及与其他信号通路相关的潜在基因调控网络有关的全面科学发现，为研究人员提供了将已确定的靶分子进一步整合到临床治疗骨骼疾病的治疗策略中的可能性。
