Osteoblastic molecular scaffold Gab1 is required for maintaining bone homeostasis.
The Grb2-associated binder 1 (Gab1), which serves as a scaffolding adaptor protein, plays a crucial role in transmitting key signals that control cell growth, differentiation and function from multiple receptors. However, its biological role in osteoblast activity and postnatal bone metabolism remains unclear. To elucidate the in vivo function of Gab1 in postnatal bone remodeling, we generated osteoblast-specific Gab1 knockout mice. Disruption of Gab1 expression in osteoblasts led to decreased trabecular bone mass with a reduced bone formation rate and a decreased bone resorption. Bones from Gab1 mutants also exhibited inferior mechanical properties. Moreover, primary osteoblasts from Gab1 mutant mice demonstrated markedly suppressed osteoblast mineralization, increased susceptibility to apoptosis and decreased expression of receptor activator of NF-kappaB ligand (RANKL). Activation of serine-threonine Akt kinase and extracellular signal-regulated kinase in response to insulin and insulin-like growth factor 1 was attenuated in Gab1 mutant osteoblasts. Our results show that Gab1-mediated signals in osteoblasts are crucial for normal postnatal bone homeostasis.
Weng
Tujun
T
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, PR China.
Mao
Fengfeng
F
Wang
Youliang
Y
Sun
Qiang
Q
Li
Ruixin
R
Yang
Guan
G
Zhang
Xizheng
X
Luo
Jincai
J
Feng
Gen-Sheng
GS
Yang
Xiao
X
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001696:Biomechanical Phenomena / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D015519:Bone Density / Q000235:genetics / Q000502:physiology; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D014057:Tomography, X-Ray Computed
D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D053245:RANK Ligand