Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
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WNT16基因座是人类皮质骨厚度和非脊椎骨折风险的主要决定因素。椎间盘突出引起的非脊椎骨折造成的残疾、死亡率和费用是巨大的。我们在这里证明，Wnt16缺陷小鼠自发骨折的结果，低皮质厚度和高皮质孔隙度。相比之下，这些小鼠的骨小梁体积没有改变。机制研究表明，WNT 16是成骨细胞衍生的，并通过直接作用于破骨细胞祖细胞和间接增加成骨细胞中骨保护素（Opg）的表达来抑制人和小鼠破骨细胞的发生。在破骨细胞祖细胞中由WNT 16激活的信号通路是非经典的，而在成骨细胞中激活的通路是经典和非经典的。有条件的Wnt16失活表明，成骨细胞系细胞是WNT16的主要来源，其在成骨细胞中的靶向缺失增加了骨折易感性。因此，成骨细胞衍生的WNT16是以前未报道的破骨细胞生成和骨折易感性的关键调节因子。这些发现为非脊椎骨折的具体预防或治疗开辟了新的途径，这是一个尚未满足的医疗需求。
The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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