c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Nat Commun. 2012 Jan 17;3:630. doi: 10.1038/ncomms1651.

Abstract

Interleukin-6 (IL-6) and c-Src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-Src stimulates IL-6 expression through the STAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-Src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-Src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-Src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / metabolism
  • CSK Tyrosine-Protein Kinase
  • Cell Differentiation
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Regulation*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism*
  • Interleukin-6 / metabolism*
  • Mice
  • Models, Biological
  • Osteoblasts / cytology*
  • Osteoblasts / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference
  • STAT3 Transcription Factor / metabolism
  • Time Factors
  • src-Family Kinases

Substances

  • Core Binding Factor Alpha 1 Subunit
  • Culture Media, Conditioned
  • Insulin-Like Growth Factor Binding Protein 5
  • Interleukin-6
  • Runx2 protein, mouse
  • STAT3 Transcription Factor
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human