PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation

Jianwen Wei, Xiaoyi Sheng, Daorong Feng, Barbara McGrath, Douglas R. Cavener

Research output: Contribution to journalArticle

83 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)693-707
Number of pages15
JournalJournal of Cellular Physiology
Volume217
Issue number3
DOIs
StatePublished - Dec 2008
Externally publishedYes

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Osteoblasts
Collagen Type I
Prokaryotic Initiation Factor-2
Cyclin D
Eukaryotic Initiation Factors
Cyclin A
Procollagen
Cyclin E
Defects
Cell proliferation
Medical problems
Endoplasmic Reticulum
Cell Cycle
Bone
Phosphotransferases
Collagen
Cells
Cell Proliferation
Tissue
Bone and Bones

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. / Wei, Jianwen; Sheng, Xiaoyi; Feng, Daorong; McGrath, Barbara; Cavener, Douglas R.

In: Journal of Cellular Physiology, Vol. 217, No. 3, 12.2008, p. 693-707.

Research output: Contribution to journalArticle

Wei, Jianwen ; Sheng, Xiaoyi ; Feng, Daorong ; McGrath, Barbara ; Cavener, Douglas R. / PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. In: Journal of Cellular Physiology. 2008 ; Vol. 217, No. 3. pp. 693-707.
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