Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta

Nat Med. 2014 Jun;20(6):670-5. doi: 10.1038/nm.3544. Epub 2014 May 4.

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder, in both a dominant and recessive manner, of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms. Here, we show that excessive transforming growth factor-β (TGF-β) signaling is a mechanism of OI in both recessive (Crtap(-/-)) and dominant (Col1a2(tm1.1Mcbr)) OI mouse models. In the skeleton, we find higher expression of TGF-β target genes, higher ratio of phosphorylated Smad2 to total Smad2 protein and higher in vivo Smad2 reporter activity. Moreover, the type I collagen of Crtap(-/-) mice shows reduced binding to the small leucine-rich proteoglycan decorin, a known regulator of TGF-β activity. Anti-TGF-β treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI and improves the lung abnormalities in Crtap(-/-) mice. Hence, altered TGF-β matrix-cell signaling is a primary mechanism in the pathogenesis of OI and could be a promising target for the treatment of OI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Collagen Type I / genetics
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Immunoblotting
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Chaperones
  • Osteogenesis Imperfecta / metabolism
  • Osteogenesis Imperfecta / physiopathology*
  • Proteins / genetics
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Surface Plasmon Resonance
  • Transforming Growth Factor beta / metabolism*
  • X-Ray Microtomography

Substances

  • Collagen Type I
  • Crtap protein, mouse
  • Molecular Chaperones
  • Proteins
  • Transforming Growth Factor beta