Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033, USA.
J Bone Miner Res. 2012 Nov;27(11):2359-72. doi: 10.1002/jbmr.1687.
Connexin 43 (Cx43) is the most abundant gap junction protein in bone and has been demonstrated as an integral component of skeletal homeostasis. In the present study, we sought to further refine the role of Cx43 in the response to mechanical unloading by subjecting skeletally mature mice with a bone-specific deletion of Cx43 (cKO) to 3 weeks of mechanical unloading via hindlimb suspension (HLS). The HLS model was selected to recapitulate the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity. At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with expanded cortices, decreased cortical thickness, decreased bone mineral density, and increased porosity. There was no baseline trabecular phenotype. After 3 weeks of HLS, wild-type (WT) mice experienced a substantial decline in trabecular bone volume fraction, connectivity density, trabecular thickness, and trabecular tissue mineral density. These deleterious effects were attenuated in cKO mice. Conversely, there was a similar and significant amount of cortical bone loss in both WT and cKO. Interestingly, mechanical testing revealed a greater loss of strength and rigidity for cKO during HLS. Analysis of double-label quantitative histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate at both the periosteal and endocortical surfaces of the femur after unloading of WT mice. This suppression of bone formation was not observed in cKO mice, in which parameters were maintained at baseline levels. Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation. Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age-related and unloading-induced bone loss.
间隙连接蛋白 43（Cx43）是骨骼中含量最丰富的缝隙连接蛋白，已被证明是骨骼动态平衡的重要组成部分。在本研究中，我们通过对骨骼成熟的 Cx43 特异性敲除（cKO）小鼠进行 3 周的后肢悬吊（HLS）机械去负荷，进一步探讨 Cx43 在机械去负荷反应中的作用。选择 HLS 模型来模拟由于长时间卧床休息、与衰老相关的活动减少以及太空微重力引起的骨骼去负荷的影响。在基线时，cKO 小鼠的皮质骨表现出骨质疏松表型，表现为皮质扩张、皮质厚度降低、骨密度降低和孔隙率增加。基线时没有小梁表型。经过 3 周的 HLS，野生型（WT）小鼠的小梁骨体积分数、连接密度、小梁厚度和小梁组织骨密度显著下降。这些有害影响在 cKO 小鼠中减弱。相反，WT 和 cKO 小鼠的皮质骨丢失量相似且显著。有趣的是，机械测试显示在 HLS 期间 cKO 的强度和刚性损失更大。双标记定量组织形态计量学数据分析表明，WT 小鼠去负荷后，股骨的骨皮质和骨内膜表面的骨形成率、矿化表面和矿化沉积率均显著降低。在 cKO 小鼠中没有观察到这种骨形成的抑制，其参数保持在基线水平。综上所述，本研究结果表明 Cx43 缺乏使骨骼对机械去负荷的作用脱敏，这可能是由于机械敏感的成骨细胞无法有效地将去负荷状态传递给成骨细胞以抑制骨形成。Cx43 可能代表一种新的治疗靶点，可作为研究年龄相关性和去负荷诱导性骨丢失的对策。
