Critical roles of the TGF-β type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development

Tomoya Matsunobu, Kiyoyuki Torigoe, Masaki Ishikawa, Susana de Vega, Ashok B. Kulkarni, Yukihide Iwamoto, Yoshihiko Yamada

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

TGF-β has been implicated in the proliferation and differentiation of chondrocytes and osteoblasts. However, the in vivo function of TGF-β in skeletal development is unclear. In this study, we investigated the role of TGF-β signaling in growth plate development by creating mice with a conditional knockout of the TGF-β type I receptor ALK5 (ALK5CKO) in skeletal progenitor cells using Dermo1-Cre mice. ALK5CKO mice had short and wide long bones, reduced bone collars, and trabecular bones. In ALK5CKO growth plates, chondrocytes proliferated and differentiated, but ectopic cartilaginous tissues protruded into the perichondrium. In normal growth plates, ALK5 protein was strongly expressed in perichondrial progenitor cells for osteoblasts, and in a thin chondrocyte layer located adjacent to the perichondrium in the peripheral cartilage. ALK5CKO growth plates had an abnormally thin perichondrial cell layer and reduced proliferation and differentiation of osteoblasts. These defects in the perichondrium likely caused the short bones and ectopic cartilaginous protrusions. Using tamoxifen-inducible Cre-ER™-mediated ALK5-deficient primary calvarial cell cultures, we found that TGF-β signaling promoted osteoprogenitor proliferation, early differentiation, and commitment to the osteoblastic lineage through the selective MAPKs and Smad2/3 pathways. These results demonstrate the important roles of TGF-β signaling in perichondrium formation and differentiation, as well as in growth plate integrity during skeletal development.

Original languageEnglish
Pages (from-to)325-338
Number of pages14
JournalDevelopmental Biology
Volume332
Issue number2
DOIs
Publication statusPublished - 2009 Aug 15

Keywords

  • ALK5 (TGF-β type I receptor)
  • Chondrocytes
  • Conditional knockout mice
  • Growth plate
  • Osteoblasts
  • Perichondrium
  • Skeletal progenitor cells

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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