Aberrant activation of Wnt signaling pathway altered osteocyte mineralization
Aberrant activation of Wnt signaling pathway altered osteocyte mineralization
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Wnt 信号通路的异常激活改变了骨细胞矿化
DOI：
10.1016/j.bone.2019.06.027
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发表时间：
2019
期刊：
影响因子：
4.1
通讯作者：
Xiao Yin
中科院分区：
文献类型：
--
作者：
Zhou Yinghong;Lin Jinying;Shao Jin;Zuo Qiliang;Wang Shengfang;Wolff Annalena;Dung Trung Nguyen;Rintoul Llew;Du Zhibin;Gu Yuantong;Peng Yong Y.;Ramshaw John A. M.;Long Xing;Xiao Yin
骨矿化是一个动态过程，涉及细胞、分泌大分子、信号通路和酶促反应之间复杂的相互作用；骨矿化的失调可能导致严重的骨骼疾病，包括低磷血症佝偻病、骨质疏松症和类风湿性关节炎。很少有研究报道骨细胞在骨矿化中的作用，骨细胞是骨骼系统中最丰富的骨细胞，也是骨重塑的主要策划者，这是由于它们深深嵌入矿化骨基质的性质。Wnt/β-catenin信号通路积极参与各种生命过程，包括成骨；然而，Wnt/β-catenin信号在骨末端矿化中的作用，特别是在骨细胞的调节中，在很大程度上是未知的。本研究表明，在矿化末端过程中，Wnt/β-catenin通路下调，当骨细胞中Wnt/β-catenin信号被激活时，树突发育受到抑制，牙本质基质蛋白1 （DMP1）的表达受到抑制。骨细胞中Wnt/β-catenin信号的异常激活导致胶原原纤维表面自发沉积超大矿化结节。矿物晶体结构的改变和矿物与有机基质之间的结合力降低表明矿物与胶原蛋白的结合较差。综上所述，Wnt/β-catenin信号在骨细胞的终末分化中起着至关重要的作用，因此，靶向骨细胞中的Wnt/β-catenin信号可能是治疗骨相关疾病的潜在治疗方法。
Mineralization of bone is a dynamic process, involving a complex interplay between cells, secreted macromolecules, signaling pathways, and enzymatic reactions; the dysregulation of bone mineralization may lead to serious skeletal disorders, including hypophosphatemic rickets, osteoporosis, and rheumatoid arthritis. Very few studies have reported the role of osteocytes — the most abundant bone cells in the skeletal system and the major orchestrators of bone remodeling in bone mineralization, which is owed to their nature of being deeply embedded in the mineralized bone matrix. The Wnt/β-catenin signaling pathway is actively involved in various life processes including osteogenesis; however, the role of Wnt/β-catenin signaling in the terminal mineralization of bone, especially in the regulation of osteocytes, is largely unknown. This research demonstrates that during the terminal mineralization process, the Wnt/β-catenin pathway is downregulated, and when Wnt/β-catenin signaling is activated in osteocytes, dendrite development is suppressed and the expression of dentin matrix protein 1 (DMP1) is inhibited. Aberrant activation of Wnt/β-catenin signaling in osteocytes leads to the spontaneous deposition of extra-large mineralized nodules on the surface of collagen fibrils. The altered mineral crystal structure and decreased bonding force between minerals and the organic matrix indicate the inferior integration of minerals and collagen. In conclusion, Wnt/β-catenin signaling plays a critical role in the terminal differentiation of osteocytes and as such, targeting Wnt/β-catenin signaling in osteocytes may serve as a potential therapeutic approach for the management of bone-related diseases.