title: Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Grafe
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Alexander
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Homan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Caressa
authors.initials: C
authors.lastname: Lietman
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Howard Hughes Medical Institute, Houston, Texas, USA.
authors.forename: Ming Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Howard Hughes Medical Institute, Houston, Texas, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.affiliation: 1] Research Department, Shriners Hospital for Children, Portland, Oregon, USA. [2] Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Weis
authors.affiliation: Genzyme Research Center, Framingham, Massachusetts, USA.
authors.forename: T Kuber
authors.initials: TK
authors.lastname: Sampath
authors.affiliation: Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ambrose
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: Eyre
authors.affiliation: 1] Research Department, Shriners Hospital for Children, Portland, Oregon, USA. [2] Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Bächinger
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Howard Hughes Medical Institute, Houston, Texas, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D016326:Extracellular Matrix Proteins; D005260:Female; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D010013:Osteogenesis Imperfecta / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020349:Surface Plasmon Resonance; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D024042:Collagen Type I; C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D018832:Molecular Chaperones; D011506:Proteins; D016212:Transforming Growth Factor beta