Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation
Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation
复制标题
破骨细胞中 Wnt5a 的缺失会导致骨形成减少而导致骨质流失
DOI：
10.1111/nyas.14293
复制
发表时间：
2020-01-09
影响因子：
5.2
通讯作者：
Drissi, Hicham
中科院分区：
文献类型：
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作者：
Roberts, Joseph L.;Liu, Guanglu;Drissi, Hicham
骨重塑是通过破骨细胞和成骨细胞的耦合活动来实现的，这些活动受到许多局部产生的分泌因子（包括 WNT5A）的控制。虽然之前的研究表明，成骨细胞来源的 WNT5A 可以促进破骨细胞生成，但破骨细胞来源的 WNT5A 在骨重塑中的功能尚未被探索。我们通过利用组织蛋白酶 K-Cre (Ctsk-Cre) 小鼠有条件地删除成熟破骨细胞中的 Wnt5a，研究了破骨细胞衍生的 WNT5A 对骨稳态的影响。这些小鼠表现出骨小梁和皮质骨减少。低骨量表型是由骨形成减少引起的，而不是破骨细胞介导的骨吸收，因为破骨细胞数量和血清 CTX 标记物没有变化。此外，对破骨细胞和成骨细胞衍生的 WNT5A 进行分子分析，发现丝氨酸磷酸化的 WNT5A 是经 RANKL 处理的模仿破骨细胞的巨噬细胞所独有的。这项研究提出了一种新的范式，其中 WNT5A 对依赖于来源细胞的骨重塑具有相反的作用，这种作用可能是由 WNT5A 的细胞类型特异性差异翻译后修饰引起的。
Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast-derived WNT5A promotes osteoclastogenesis, the function of osteoclast-derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast-derived WNT5A on bone homeostasis by utilizing the Cathepsin K-Cre (Ctsk-Cre) mouse to conditionally delete Wnt5a in mature osteoclasts. These mice exhibited reduced trabecular and cortical bone. The low bone-mass phenotype was driven by decreased bone formation, not osteoclast-mediated bone resorption, as osteoclast number and serum CTX marker were unchanged. Furthermore, molecular analysis of osteoclast- and osteoblast-derived WNT5A identified a serine-phosphorylated WNT5A that is unique to RANKL-treated macrophages mimicking osteoclasts. This study suggests a new paradigm in which WNT5A has opposing effects on bone remodeling that are dependent on the cell of origin, an effect that may result from cell type-specific differential posttranslational modifications of WNT5A.