Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
J Cell Mol Med. 2018 Feb;22(2):849-860. doi: 10.1111/jcmm.13370. Epub 2017 Oct 27.
The G12 family of G protein alpha subunits has been shown to participate in the regulation of various physiological processes. However, the role of Gα12 in bone physiology has not been well described. Here, by micro-CT analysis, we discovered that Gα12-knockout mice have an osteopetrotic phenotype. Histological examination showed lower osteoclast number in femoral tissue of Gα12-knockout mice compared to wild-type mice. Additionally, in vitro osteoclastic differentiation of precursor cells with receptor activator of nuclear factor-κB ligand (RANKL) showed that Gα12 deficiency decreased the number of osteoclast generated and the bone resorption activity. The induction of nuclear factor of activated T-cell c1 (NFATc1), the key transcription factor of osteoclastogenesis, and the activation of RhoA by RANKL was also significantly suppressed by Gα12 deficiency. We further found that the RANKL induction of NFATc1 was not dependent on RhoA signalling, while osteoclast precursor migration and bone resorption required RhoA in the Gα12-mediated regulation of osteoclasts. Therefore, Gα12 plays a role in differentiation through NFATc1 and in cell migration and resorption activity through RhoA during osteoclastogenesis.
G 蛋白α亚基 G12 家族被证实参与了多种生理过程的调节。然而，Gα12 在骨生理学中的作用尚未得到充分描述。在这里，通过 micro-CT 分析，我们发现 Gα12 敲除小鼠表现出成骨过度的表型。组织学检查显示，与野生型小鼠相比，Gα12 敲除小鼠股骨组织中的破骨细胞数量较少。此外，用核因子κB 受体激活剂配体（RANKL）诱导前体细胞的体外破骨细胞分化显示，Gα12 缺失减少了生成的破骨细胞数量和骨吸收活性。核因子活化 T 细胞 c1（NFATc1）的诱导，破骨细胞生成的关键转录因子，以及 RANKL 对 RhoA 的激活也被 Gα12 缺失显著抑制。我们进一步发现，RANKL 诱导的 NFATc1 不依赖于 RhoA 信号通路，而破骨细胞前体的迁移和骨吸收在 Gα12 介导的破骨细胞调节中需要 RhoA。因此，Gα12 在破骨细胞分化中通过 NFATc1 发挥作用，在细胞迁移和骨吸收活性中通过 RhoA 发挥作用。
