Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, Massachusetts 02114, USA.
J Clin Invest. 2011 Sep;121(9):3492-504. doi: 10.1172/JCI46406. Epub 2011 Aug 1.
The heterotrimeric G protein subunit Gsα stimulates cAMP-dependent signaling downstream of G protein-coupled receptors. In this study, we set out to determine the role of Gsα signaling in cells of the early osteoblast lineage in vivo by conditionally deleting Gsα from osterix-expressing cells. This led to severe osteoporosis with fractures at birth, a phenotype that was found to be the consequence of impaired bone formation rather than increased resorption. Osteoblast number was markedly decreased and osteogenic differentiation was accelerated, resulting in the formation of woven bone. Rapid differentiation of mature osteoblasts into matrix-embedded osteocytes likely contributed to depletion of the osteoblast pool. In addition, the number of committed osteoblast progenitors was diminished in both bone marrow stromal cells (BMSCs) and calvarial cells of mutant mice. In the absence of Gsα, expression of sclerostin and dickkopf1 (Dkk1), inhibitors of canonical Wnt signaling, was markedly increased; this was accompanied by reduced Wnt signaling in the osteoblast lineage. In summary, we have shown that Gsα regulates bone formation by at least two distinct mechanisms: facilitating the commitment of mesenchymal progenitors to the osteoblast lineage in association with enhanced Wnt signaling; and restraining the differentiation of committed osteoblasts to enable production of bone of optimal mass, quality, and strength.
三聚体 G 蛋白亚基 Gsα 刺激 G 蛋白偶联受体下游的 cAMP 依赖性信号转导。在这项研究中，我们通过条件性删除成骨特异性转录因子（osterix）表达细胞中的 Gsα，旨在确定 Gsα 信号在成骨细胞早期谱系细胞中的作用。这导致了出生时就发生严重的骨质疏松症和骨折，该表型是由于骨形成受损而不是吸收增加所致。成骨细胞数量明显减少，成骨分化加速，导致编织骨形成。成熟成骨细胞快速分化为基质嵌入的骨细胞，可能导致成骨细胞池耗竭。此外，突变小鼠的骨髓基质细胞（BMSCs）和成颅骨细胞中的成骨细胞祖细胞数量减少。在缺乏 Gsα 的情况下，经典 Wnt 信号通路抑制剂骨硬化素和 Dickkopf1（Dkk1）的表达显著增加；这伴随着成骨细胞谱系中 Wnt 信号的减少。总之，我们已经表明，Gsα 通过至少两种不同的机制来调节骨形成：通过增强 Wnt 信号促进间充质祖细胞向成骨细胞谱系的定向分化；并抑制成骨细胞的分化，以产生具有最佳质量、强度和数量的骨。
