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

Nature Medicine volume 20, pages 670–675 (2014)Cite this article

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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 manifestations1. 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 pathomechanisms2. Here, we show that excessive transforming growth factor-β (TGF-β) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) 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 activity3,4. 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.

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Figure 1: Excessive TGF-β signaling in Crtap−/− mice.
Figure 2: Phenotypic correction of Crtap−/− mice after treatment with the TGF-β neutralizing antibody 1D11.
Figure 3: Reduced decorin binding to type I collagen of Crtap−/− mice.
Figure 4: Inhibition of upregulated TGF-β signaling improves the bone phenotype in a mouse model of dominant OI (Col1a2tm1.1Mcbr).

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Acknowledgements

We thank D. Spencer and his lab (Baylor College of Medicine) for providing the IVIS camera system and training, M. Starbuck and F. Gannon for consultation and advice in bone histomorphometry, M. Warman and C. Jacobsen (Boston Children's Hospital) for providing the Col1a2tm1.1Mcbr mice and helpful information. We also thank L. Fisher (US National Institute of Dental and Craniofacial Research) for providing the decorin antibody LF-113. We thank M. Bagos for help with microCT analyses, A. Abraham for help with the biomechanical testing, W. Song and S. Liu for their help with serum bone turnover analyses, the US National Institutes of Health (NIH) for providing the ImageJ software and A. Choi and H. Lam (Harvard Medical School) for providing the ImageJ modification for lung morphometry, which was generated by P. Thompson. Also, we thank D. Rifkin (New York University Medical Center) for providing PAI-luciferase reporter mink lung epithelial cells. In addition, we thank R. Morello, G. Sule, D. Baldridge and G. Ghosal for their helpful discussions and P. Fonseca for editorial assistance. This work was supported by a research fellowship from the German Research Foundation/Deutsche Forschungsgemeinschaft (I.G.), a Michael Geisman Fellowship from the Osteogenesis Imperfecta Foundation (I.G.), grant support from Shriners Hospitals for Children (H.P.B.), NIH grants 5F31DE020954 (E.P.H.), 5F31DE022483 (C.L.), R37 AR037318 and R01 AR036794 (D.E.), and P01 HD70394 (B.L. and D.E.) and the Howard Hughes Medical Institute Foundation (B.L.). This work was also supported by the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (HD024064), the Eunice Kennedy Shriver US National Institute of Child Health & Human Development and the Rolanette and Berdon Lawrence Bone Disease Program of Texas.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Ingo Grafe, Tao Yang, Stefanie Alexander, Erica P Homan, Caressa Lietman, Ming Ming Jiang, Terry Bertin, Elda Munivez, Yuqing Chen, Brian Dawson & Brendan Lee

  2. Howard Hughes Medical Institute, Houston, Texas, USA

    Ming Ming Jiang, Brian Dawson & Brendan Lee

  3. Research Department, Shriners Hospital for Children, Portland, Oregon, USA

    Yoshihiro Ishikawa & Hans Peter Bächinger

  4. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA

    Yoshihiro Ishikawa & Hans Peter Bächinger

  5. Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, USA

    Mary Ann Weis & David Eyre

  6. Genzyme Research Center, Framingham, Massachusetts, USA

    T Kuber Sampath

  7. Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Catherine Ambrose

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  1. Ingo Grafe
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Contributions

I.G. and B.L. conceptualized the study. T.Y., T.K.S., C.A., D.E. and H.P.B. contributed to the design of the study and experiments. I.G., T.Y., S.A., E.P.H., C.L., M.M.J., T.B., E.M., Y.C., B.D., Y.I., M.A.W. and C.A. performed and analyzed experiments. I.G., T.Y. and B.L. wrote the manuscript with contributions from all authors. B.L. supervised the project.

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Correspondence to Brendan Lee.

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Competing interests

T.K.S. is an employee of Genzyme/Sanofi.

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Grafe, I., Yang, T., Alexander, S. et al. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med 20, 670–675 (2014). https://doi.org/10.1038/nm.3544

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