Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
PLoS One. 2011;6(8):e23516. doi: 10.1371/journal.pone.0023516. Epub 2011 Aug 29.
Emerging evidence suggests that connexin mediated gap junctional intercellular communication contributes to many aspects of bone biology including bone development, maintenance of bone homeostasis and responsiveness of bone cells to diverse extracellular signals. Deletion of connexin 43, the predominant gap junction protein in bone, is embryonic lethal making it challenging to examine the role of connexin 43 in bone in vivo. However, transgenic murine models in which only osteocytes and osteoblasts are deficient in connexin 43, and which are fully viable, have recently been developed. Unfortunately, the bone phenotype of different connexin 43 deficient models has been variable. To address this issue, we used an osteocalcin driven Cre-lox system to create osteoblast and osteocyte specific connexin 43 deficient mice. These mice displayed bone loss as a result of increased bone resorption and osteoclastogenesis. The mechanism underlying this increased osteoclastogenesis included increases in the osteocytic, but not osteoblastic, RANKL/OPG ratio. Previous in vitro studies suggest that connexin 43 deficient bone cells are less responsive to biomechanical signals. Interestingly, and in contrast to in vitro studies, we found that connexin 43 deficient mice displayed an enhanced anabolic response to mechanical load. Our results suggest that transient inhibition of connexin 43 expression and gap junctional intercellular communication may prove a potentially powerful means of enhancing the anabolic response of bone to mechanical loading.
新出现的证据表明，连接子介导的缝隙连接细胞间通讯有助于骨生物学的许多方面，包括骨发育、骨稳态的维持以及骨细胞对多种细胞外信号的反应性。连接子 43 的缺失，即骨骼中主要的缝隙连接蛋白，在胚胎期是致命的，这使得研究连接子 43 在体内的骨作用具有挑战性。然而，最近已经开发出了仅在成骨细胞和骨细胞中缺乏连接子 43 的转基因小鼠模型，这些模型是完全有活力的。不幸的是，不同的连接子 43 缺乏模型的骨表型一直存在差异。为了解决这个问题，我们使用骨钙素驱动的 Cre-lox 系统来创建成骨细胞和骨细胞特异性的连接子 43 缺乏小鼠。这些小鼠由于骨吸收和破骨细胞生成增加而出现骨丢失。这种破骨细胞生成增加的机制包括骨源性，而不是成骨细胞，RANKL/OPG 比值的增加。以前的体外研究表明，连接子 43 缺乏的骨细胞对生物力学信号的反应性较低。有趣的是，与体外研究相反，我们发现连接子 43 缺乏的小鼠对机械负荷表现出增强的合成代谢反应。我们的结果表明，连接子 43 表达和缝隙连接细胞间通讯的短暂抑制可能成为增强骨对机械负荷的合成代谢反应的一种潜在有效手段。
