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New perspectives on osteogenesis imperfecta

Nature Reviews Endocrinology volume 7, pages 540–557 (2011)Cite this article

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Abstract

A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell–cell and cell–matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future.

Key Points

  • Osteogenesis imperfecta is a collagen-related disorder characterized by low bone mass, decreased bone strength and increased bone fragility

  • Dominant osteogenesis imperfecta is caused by defects in the quantity or structure of type I procollagen, which affects bone at multiple levels, for example, matrix structure and mineralization

  • Recessive osteogenesis imperfecta is caused by deficiency of proteins that interact with collagen and affect its post-translational modification or folding, such as CRTAP, P3H1 and PPIB and Serpin H1 and FKBP10

  • Common features of dominant and recessive osteogenesis imperfecta, for example, delayed collagen folding, effects on bone and cartilage or increased endoplasmic reticulum stress, may be the key to understanding its pathogenesis

  • Clinical management of osteogenesis imperfecta should involve a multidisciplinary team that provides physical rehabilitation, genetic, hearing, dental, neurological, endocrine and surgical management

  • Bisphosphonates are widely administered to individuals with osteogenesis imperfecta, with positive effects on bone mass and vertebral geometry, but cause a decline in bone material quality

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Figure 1: Mechanisms contributing to autosomal dominant osteogenesis imperfecta bone dysplasia: from mutant type I collagen gene to bone defect.
Figure 2: Distribution of lethal and nonlethal glycine substitutions that cause osteogenesis imperfecta along the type I collagen monomer and fibril.
Figure 3: Electrophoretic analysis of type I collagen synthesized by dermal fibroblasts with mutations in genes coding for collagen 3-hydroxylation complex components.
Figure 4: Relationship between dominant and recessive forms of osteogenesis imperfecta.

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Acknowledgements

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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  1. Department of Biochemistry, Section of Medicine and Pharmacy, University of Pavia, Via Taramelli 3/B, 27100, Pavia, Italy

    Antonella Forlino

  2. Bone and Extracellular Matrix Branch, NICHD, NIH, Building 10; Room 10N260, 9000 Rockville Pike, Bethesda, 20892, MD, USA

    Wayne A. Cabral, Aileen M. Barnes & Joan C. Marini

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  1. Antonella Forlino
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  2. Wayne A. Cabral
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  3. Aileen M. Barnes
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All authors researched the data for the article, provided substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Joan C. Marini.

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Forlino, A., Cabral, W., Barnes, A. et al. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 7, 540–557 (2011). https://doi.org/10.1038/nrendo.2011.81

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