The Gsα/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsα due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsα have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of Gsα^R201C driven by the Adiponectin (Adq) promoter. Adq-Gsα^R201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, Gsα^R201C caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, Gsα^R201C, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, Gsα^R201C caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsα/cAMP pathway is a major modulator of both functions.

Gsα/cAMP 信号通路介导多种激素和调节产后骨骼稳态的因子的作用。因此，由于功能获得性突变 (R201C/R201H) 导致的 Gsα 活性失调导致整个骨/骨髓器官的严重结构和功能紊乱。虽然 Gsα 功能获得性突变的后果已在成骨细胞和处于不同分化阶段的骨髓骨祖细胞中进行了广泛研究，但它们对脂肪形成的骨髓基质细胞的影响仍未得到解决。我们生成了由脂联素( Adq ) 启动子驱动的Gs α ^{R201C表达的小鼠模型。}广告-Gs α ^R201C小鼠产生了干骺端、骨干和皮质骨变化的复杂组合。在干骺端，Gs α ^R201C引起骨吸收的早期阶段，然后是骨沉积。干骺端骨形成由Adq-Cre追踪的细胞维持，并最终导致高小梁骨量表型。在骨干中，Gs α ^R201C与雌激素结合，触发以Adq - Cre为靶点的血管周围骨髓基质细胞的成骨活性，从而导致髓内骨形成。最后，与之前未被注意到的Adq存在一致-骨内血管中的Cre标记的周细胞， Gsα ^R201C导致了影响皮质（增加的孔隙率）和小梁（隧道吸收）骨的溶解表型的发展。这些结果提供了第一个证据，即骨骼中的Adq细胞网络不仅调节骨吸收，而且有助于骨形成，并且 Gs α /cAMP 途径是这两种功能的主要调节剂。