Javaheri Behzad, Stern Amber Rath, Lara Nuria, Dallas Mark, Zhao Hong, Liu Ying, Bonewald Lynda F, Johnson Mark L
The Royal Veterinary College, London, UK.
J Bone Miner Res. 2014 Mar;29(3):705-15. doi: 10.1002/jbmr.2064.
The Wnt/β-catenin signaling pathway is essential for bone cell viability and function and for skeletal integrity. To determine if β-catenin in osteocytes plays a role in the bone anabolic response to mechanical loading, 18- to 24-week-old osteocyte β-catenin haploinsufficient mice (Dmp1-Cre × β-catenin fl/ + ; HET cKO) were compared with their β-catenin fl/fl (control) littermates. Trabecular bone volume (BV/TV) was significantly less (58.3%) in HET cKO females versus controls, whereas male HET cKO and control mice were not significantly different. Trabecular number was significantly less in HET cKO mice compared with controls for both genders, and trabecular separation was greater in female HET cKO mice. Osteoclast surface was significantly greater in female HET cKO mice. Cortical bone parameters in males and females showed subtle or no differences between HET cKO and controls. The right ulnas were loaded in vivo at 100 cycles, 2 Hz, 2500 µϵ, 3 days per week for 3 weeks, and the left ulnas served as nonloaded controls. Calcein and alizarin complexone dihydrate were injected 10 days and 3 days before euthanization, respectively. Micro-computed tomography (µCT) analysis detected an 8.7% and 7.1% increase in cortical thickness in the loaded right ulnas of male and female control mice, respectively, compared with their nonloaded left ulnas. No significant increase in new cortical bone formation was observed in the HET cKO mice. Histomorphometric analysis of control mice showed a significant increase in endocortical and periosteal mineral apposition rate (MAR), bone-formation rate/bone surface (BFR/BS), BFR/BV, and BFR/TV in response to loading, but no significant increases were detected in the loaded HET cKO mice. These data show that deleting a single copy of β-catenin in osteocytes abolishes the anabolic response to loading, that trabecular bone in females is more severely affected and suggest that a critical threshold of β-catenin is required for bone formation in response to mechanical loading.
Wnt/β-连环蛋白信号通路对于骨细胞的生存能力和功能以及骨骼完整性至关重要。为了确定骨细胞中的β-连环蛋白是否在对机械负荷的骨合成代谢反应中发挥作用，将18至24周龄的骨细胞β-连环蛋白单倍体不足小鼠（Dmp1-Cre×β-连环蛋白fl/+；HET cKO）与其β-连环蛋白fl/fl（对照）同窝小鼠进行比较。与对照组相比，HET cKO雌性小鼠的小梁骨体积（BV/TV）显著减少（58.3%），而雄性HET cKO小鼠和对照小鼠之间无显著差异。与对照组相比，HET cKO小鼠的小梁数量在两性中均显著减少，雌性HET cKO小鼠的小梁间距更大。雌性HET cKO小鼠的破骨细胞表面显著更大。雄性和雌性的皮质骨参数在HET cKO小鼠和对照小鼠之间显示出细微差异或无差异。对右侧尺骨进行体内加载，频率为100次循环、2赫兹、2500微应变，每周3天，共3周，左侧尺骨作为未加载对照。分别在安乐死10天和3天前注射钙黄绿素和茜素络合物二水合物。微计算机断层扫描（µCT）分析检测到，与未加载的左侧尺骨相比，雄性和雌性对照小鼠加载的右侧尺骨皮质厚度分别增加了8.7%和7.1%。在HET cKO小鼠中未观察到新皮质骨形成的显著增加。对照小鼠的组织形态计量学分析显示，加载后内皮质和骨膜矿物质沉积率（MAR）、骨形成率/骨表面（BFR/BS）、BFR/BV和BFR/TV显著增加，但在加载的HET cKO小鼠中未检测到显著增加。这些数据表明，在骨细胞中删除β-连环蛋白的一个拷贝会消除对加载的合成代谢反应，雌性小梁骨受影响更严重，并表明对机械负荷作出反应的骨形成需要β-连环蛋白的临界阈值。
