Tan Xiaohong, Weng Tujun, Zhang Jishuai, Wang Jian, Li Wenlong, Wan Haifeng, Lan Yu, Cheng Xuan, Hou Ning, Liu Haihong, Ding Jun, Lin Fuyu, Yang Ruifu, Gao Xiang, Chen Di, Yang Xiao
Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, PR China.
J Cell Sci. 2007 Jul 1;120(Pt 13):2162-70. doi: 10.1242/jcs.03466. Epub 2007 Jun 5.
Transforming growth factor beta (TGFbeta) is a multifunctional cytokine involved in skeletal development. Smad4 is the central intracellular mediator of TGFbeta signaling. Our previous studies reveal that Smad4 is required for maintaining the normal development of chondrocytes in the growth plate. However, its biological function during postnatal bone remodeling is largely unknown. To investigate the role of Smad4 in maintaining bone homeostasis, we disrupted the Smad4 gene in differentiated osteoblasts using the Cre-loxP system. The Smad4 mutant mice exhibited lower bone mass up to 6 months of age. The proliferation and function of the mutant osteoblasts were significantly decreased. Bone mineral density, bone volume, bone formation rate and osteoblast numbers were remarkably reduced in Smad4 mutants. Intriguingly, the trabecular bone volume in Smad4 mutant mice older than 7 months was higher than that of controls whereas the calvarial and cortical bone remained thinner than in controls. This correlated with reduced bone resorption possibly caused by downregulation of TGFbeta1 and alteration of the ligand receptor activator of NF-kappaB (RANKL)-osteoprotegerin (OPG) axis. These studies demonstrate essential roles of Smad4-mediated TGFbeta signaling in coupling bone formation and bone resorption and maintaining normal postnatal bone homeostasis.
转化生长因子β（TGFβ）是一种参与骨骼发育的多功能细胞因子。Smad4是TGFβ信号传导的核心细胞内介质。我们之前的研究表明，Smad4是维持生长板中软骨细胞正常发育所必需的。然而，其在出生后骨重塑过程中的生物学功能在很大程度上尚不清楚。为了研究Smad4在维持骨稳态中的作用，我们使用Cre-loxP系统在分化的成骨细胞中破坏了Smad4基因。Smad4突变小鼠在6个月龄时骨量较低。突变成骨细胞的增殖和功能显著降低。Smad4突变体的骨矿物质密度、骨体积、骨形成率和成骨细胞数量明显减少。有趣的是，7个月以上的Smad4突变小鼠的小梁骨体积高于对照组，而颅骨和皮质骨仍比对照组薄。这与可能由TGFβ1下调和核因子κB受体激活剂配体（RANKL）-骨保护素（OPG）轴改变引起的骨吸收减少有关。这些研究证明了Smad4介导的TGFβ信号在耦合骨形成和骨吸收以及维持出生后正常骨稳态中的重要作用。
