State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, PR China.
J Cell Sci. 2010 Mar 1;123(Pt 5):682-9. doi: 10.1242/jcs.058396. Epub 2010 Feb 2.
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.
Grb2 相关衔接蛋白 1（Gab1）作为支架衔接蛋白，在传递控制细胞生长、分化和功能的关键信号方面发挥着关键作用，这些信号来自多种受体。然而，其在成骨细胞活性和出生后骨代谢中的生物学作用尚不清楚。为了阐明 Gab1 在出生后骨重塑中的体内功能，我们生成了成骨细胞特异性 Gab1 敲除小鼠。成骨细胞中 Gab1 表达的破坏导致小梁骨量减少，骨形成率降低，骨吸收增加。Gab1 突变体的骨骼还表现出较差的机械性能。此外，Gab1 突变小鼠的原代成骨细胞表现出明显抑制的成骨细胞矿化、增加的细胞凋亡易感性和核因子-κB 配体（RANKL）表达减少。Gab1 突变体成骨细胞对胰岛素和胰岛素样生长因子 1 的丝氨酸-苏氨酸 Akt 激酶和细胞外信号调节激酶的激活作用减弱。我们的结果表明，Gab1 介导的成骨细胞信号对于正常出生后骨稳态至关重要。
