PERK Is Essential for Neonatal Skeletal Development to Regulate Osteoblast Proliferation and Differentiation
PERK Is Essential for Neonatal Skeletal Development to Regulate Osteoblast Proliferation and Differentiation
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DOI：
10.1002/jcp.21543
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发表时间：
2008-12-01
影响因子：
5.6
通讯作者：
Cavener, Douglas R.
中科院分区：
文献类型：
--
作者：
Wei, Jianwen;Sheng, Xiaoyi;Cavener, Douglas R.
Perk（真核翻译起始因子2 α激酶3）在人类和小鼠中的功能缺失突变导致严重的新生儿发育缺陷，包括糖尿病、生长迟缓和多发性骨骼发育不良。在PERK缺陷小鼠的细胞和分子水平上对骨组织的综合分析表明，新生Perk-/-小鼠严重骨质减少，这是由成熟成骨细胞数量不足、成骨细胞分化受损和I型胶原分泌减少引起的。Perk KO小鼠中成骨细胞分化受损与成骨细胞发育的关键调节因子Runx 2和Osterix表达降低相关。细胞增殖减少和关键细胞周期因子包括细胞周期蛋白D、细胞周期蛋白E、细胞周期蛋白A、Cdc 2和CDK 2的表达减少与突变型成骨细胞的分化缺陷平行发生。此外，I型胶原的运输和分泌受到损害，表现为I型前胶原在内质网中的异常保留，以及成熟胶原的产生和矿化减少。综上所述，这些研究确定PERK作为骨骼发育和成骨细胞生物学的一种新的调节剂。
Loss of function mutations of Perk (eukaryotic translation initiation factor 2 alpha kinase 3) in humans and mice cause severe neonatal developmental defects, including diabetes, growth retardation and multiple skeletal dysplasias. Comprehensive analyses on bone tissue, at the cellular and molecular level in PERK-deficient mice demonstrated that neonatal Perk-/- mice are severely osteopenic, which is caused by a deficiency in the number of mature osteoblasts, impaired osteoblast differentiation, and reduced type I collagen secretion. Impaired differentiation of osteoblasts in Perk KO mice was associated with decreased expression of Runx2 and Osterix, key regulators of osteoblast development. Reduced cell proliferation and reduced expression of key cell cycle factors including cyclin D, cyclin E, cyclin A, Cdc2, and CDK2 occur in parallel with the differentiation defect in mutant osteoblasts. In addition, the trafficking and secretion of type I collagen is compromised as manifested by abnormal retention of procollagen I in the endoplasmic reticulum, and reduced mature collagen production and mineralization. Taken together, these studies identify PERK as a novel regulator of skeletal development and osteoblast biology.