Wnt16 Is Associated with Age-Related Bone Loss and Estrogen Withdrawal in Murine Bone.
Wnt16 Is Associated with Age-Related Bone Loss and Estrogen Withdrawal in Murine Bone.
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DOI：
10.1371/journal.pone.0140260
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Price JS
中科院分区：
文献类型：
--
作者：
Todd H;Galea GL;Meakin LB;Delisser PJ;Lanyon LE;Windahl SH;Price JS
全基因组关联研究表明，Wnt16是控制骨矿物质密度、皮质厚度、骨强度和最终骨折风险的重要机制。Wnt16作用于成骨细胞和破骨细胞，在皮质骨中，主要来源于成骨细胞。这使我们假设低骨量可能与低水平的Wnt16表达有关，并且Wnt16表达会因合成代谢因素（包括机械负荷）而增加。因此，我们研究了Wnt16在衰老、机械加载和卸载、雌激素缺乏和替代以及雌激素受体α (ERα)耗尽等情况下的表达。实时荧光定量PCR结果显示，老龄雌鼠皮质骨和骨髓中Wnt16 mRNA表达量低于年轻雌鼠。在年轻雌性小鼠中，机械负荷的增加和减少都没有改变Wnt16的表达，尽管卵巢切除术后Wnt16的表达降低。相对于卵巢切除术，17β-雌二醇和选择性雌激素受体调节剂他莫昔芬均增加了Wnt16的表达。与野生型相比，雌性ERα-/-小鼠的Wnt16和ERβ表达增加。我们还研究了性别对Wnt16表达的潜在影响，尽管老年雄性皮质骨中的表达低于雌性，但老年雄性小鼠骨髓中的表达高于年轻小鼠。在肾脏中，我们将其作为非骨参考组织，Wnt16的表达在男性和女性中都不受年龄的影响。总之，年龄及其相关的骨质流失与Wnt16的低表达水平有关，而与废弃相关的骨质流失对Wnt16的表达没有影响。在人工负载小鼠胫骨中，我们没有观察到负载相关的Wnt16表达上调，但提供了证据表明其表达受雌激素受体信号传导的影响。这些发现表明，虽然Wnt16本身不是骨量调节的强制性因素，但它可能在影响与衰老和雌激素戒断期间骨量调节相关的途径中发挥作用。
Genome Wide Association Studies suggest that Wnt16 is an important contributor to the mechanisms controlling bone mineral density, cortical thickness, bone strength and ultimately fracture risk. Wnt16 acts on osteoblasts and osteoclasts and, in cortical bone, is predominantly derived from osteoblasts. This led us to hypothesize that low bone mass would be associated with low levels of Wnt16 expression and that Wnt16 expression would be increased by anabolic factors, including mechanical loading. We therefore investigated Wnt16 expression in the context of ageing, mechanical loading and unloading, estrogen deficiency and replacement, and estrogen receptor α (ERα) depletion. Quantitative real time PCR showed that Wnt16 mRNA expression was lower in cortical bone and marrow of aged compared to young female mice. Neither increased nor decreased (by disuse) mechanical loading altered Wnt16 expression in young female mice, although Wnt16 expression was decreased following ovariectomy. Both 17β-estradiol and the Selective Estrogen Receptor Modulator Tamoxifen increased Wnt16 expression relative to ovariectomy. Wnt16 and ERβ expression were increased in female ERα-/- mice when compared to Wild Type. We also addressed potential effects of gender on Wnt16 expression and while the expression was lower in the cortical bone of aged males as in females, it was higher in male bone marrow of aged mice compared to young. In the kidney, which we used as a non-bone reference tissue, Wnt16 expression was unaffected by age in either males or females. In summary, age, and its associated bone loss, is associated with low levels of Wnt16 expression whereas bone loss associated with disuse has no effect on Wnt16 expression. In the artificially loaded mouse tibia we observed no loading-related up-regulation of Wnt16 expression but provide evidence that its expression is influenced by estrogen receptor signaling. These findings suggest that while Wnt16 is not an obligatory contributor to regulation of bone mass per se, it potentially plays a role in influencing pathways associated with regulation of bone mass during ageing and estrogen withdrawal.