title: Smad4 is required for maintaining normal murine postnatal bone homeostasis.
abstract: 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.
authors.affiliation: Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, PR China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tan
authors.forename: Tujun
authors.initials: T
authors.lastname: Weng
authors.forename: Jishuai
authors.initials: J
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wenlong
authors.initials: W
authors.lastname: Li
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wan
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Haihong
authors.initials: H
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Ding
authors.forename: Fuyu
authors.initials: F
authors.lastname: Lin
authors.forename: Ruifu
authors.initials: R
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D053773:Transforming Growth Factor beta1