PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation
- 6 August 2008
- journal article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 217 (3), 693-707
- https://doi.org/10.1002/jcp.21543
Abstract
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. J. Cell. Physiol. 217: 693–707, 2008.Keywords
This publication has 51 references indexed in Scilit:
- PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in miceBMC Cell Biology, 2007
- ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiaeCell Metabolism, 2006
- SATB2 Is a Multifunctional Determinant of Craniofacial Patterning and Osteoblast DifferentiationCell, 2006
- Histological Analysis of GFP Expression in Murine BoneJournal of Histochemistry & Cytochemistry, 2005
- An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative StressMolecular Cell, 2003
- Diabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk−/− Mice Reveals a Role for Translational Control in Secretory Cell SurvivalMolecular Cell, 2001
- Multilineage Differentiation of Cbfa1-Deficient Calvarial Cells in VitroBiochemical and Biophysical Research Communications, 2000
- Direct Three-Dimensional Morphometric Analysis of Human Cancellous Bone: Microstructural Data from Spine, Femur, Iliac Crest, and CalcaneusJournal of Bone and Mineral Research, 1999
- Systemic and local factors and the maintenance of bone qualityCalcified Tissue International, 1993
- Osteogenesis Imperfecta after the MenopauseNew England Journal of Medicine, 1984