Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
J Biol Chem. 2012 Feb 24;287(9):6431-40. doi: 10.1074/jbc.M111.283119. Epub 2011 Dec 30.
Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.
α2β1 和 α11β1 整合素缺陷的小鼠缺乏主要的 I 型胶原受体。这些突变体在出生时大小没有明显差异，但在生命的头 4 周内会发展为侏儒症。侏儒症与较短、矿化程度较低且功能较弱的骨骼有关，而不是由生长板异常或成骨细胞功能障碍引起的。除了骨骼侏儒症，内脏器官相应地更小，表明成比例的侏儒症，并提示整体缩小是由系统性原因引起的。与胰岛素样生长因子 (IGF)-1 在生长控制和骨矿化中的关键作用一致，缺乏 α2β1 或 α11β1 或这两种整合素的小鼠血清中的循环 IGF-1 水平分别降低了正常水平的 39%、64%或 81%。低肝 IGF-1 产生是由于下丘脑生长激素释放激素表达减少，随后这些小鼠垂体中的生长激素表达减少所致。这些发现指出了胶原结合整合素受体在控制生长激素/IGF-1 依赖性生物活性中的新作用。因此，通过整合素将激素分泌与细胞外基质信号联系起来，代表了内分泌稳态控制的新概念。
