Mechanisms of GDF-5 action during skeletal development

P. H. Francis-West, A. Abdelfattah, P. Chen, C. Allen, J. Parish, R. Ladher, S. Allen, S. MacPherson, F. P. Luyten, C. W. Archer

Research output: Contribution to journalArticlepeer-review

295 Scopus citations

Abstract

Mutations in GDF-5, a member of the TGF-β superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias in humans. These syndromes are all characterised by the shortening of the appendicular skeleton and loss or abnormal development of some joints. To investigate how GDF-5 controls skeletogenesis, we overexpressed GDF-5 during chick limb development using the retrovirus, RCASBP. This resulted in up to a 37.5% increase in length of the skeletal elements, which was predominantly due to an increase in the number of chondrocytes. By injecting virus at different stages of development, we show that GDF-5 can increase both the size of the early cartilage condensation and the later developing skeletal element. Using in vitro micromass cultures as a model system to study the early steps of chondrogenesis, we show that GDF-5 increases chondrogenesis in a dose-dependent manner. We did not detect changes in proliferation. However, cell suspension cultures showed that GDF-5 might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis. In contrast, pulse labelling experiments of GDF-5-infected limbs showed that at later stages of skeletal development GDF-5 can increase proliferation of chondrocytes. Thus, here we show two mechanisms of how GDF-5 may control different stages of skeletogenesis. Finally, our data show that levels of GDF-5 expression/activity are important in controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5.

Original languageEnglish (US)
Pages (from-to)1305-1315
Number of pages11
JournalDevelopment
Volume126
Issue number6
StatePublished - Mar 1 1999

Keywords

  • Cell adhesion
  • Chondrogenesis
  • GDF-5
  • Joint
  • Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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