New perspectives on osteogenesis imperfecta

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.

Figures

Figure 1. Mechanisms contributing to autosomal dominant OI bone dysplasia: from mutant type I collagen gene to bone defect

Mutations in either COL1A1 or COL1A2 are translated into collagen α chains with abnormal structure, which delays folding of the heterotrimer and results in excess post-translational modification of the collagen helical region. Mutant procollagen chains unable to incorporate into heterotrimer are retrotranslocated into the cytosol and degraded by the ER-Associated Proteasomal (ERAD) pathway (1); fully misfolded heterotrimers with structural defects generate supramolecular aggregates that are eliminated by autophagy (2); mutant molecules with triple helical mutations are degraded through an unidentified pathway (3). Finally abnormal procollagen can be secreted, processed and incorporated in the extracellular matrix (4). The secreted mutant collagen affects fibril structure and interactions of NCPs with matrix, as well as matrix mineralization and osteoblast development and cell-cell and cell-matrix cross-talk. The overall result is bone deformity and fragility, although the relative importance of various contributions is under investigation.

Figure 2. Distribution of lethal and non-lethal glycine substitutions causing OI along the type I collagen monomer and fibril

The α1(I) chains are represented by blue coloration and the α2(I) chain by red coloration. Rectangles with hatched lines indicate the regions with predominantly non-lethal mutations located in the first quarter of both α chains. Filled rectangles symbolize the lethal regions in each chain. In the α1(I) monomer, stretches of exclusively lethal mutations were identified in the Major Ligand Binding Regions (MLBR2 and 3). In α2(I), lethal mutations were clustered in eight regions along the chain. The vertical boxes defined by dots represent the binding regions in the type I collagen fibril for keratin (KSPG), heparan (HSPG), dermatan (DSPG) and chondroitin sulphate (CSPG) proteoglycans. The monomer-binding sites for DSPG and decorin core protein overlap α2(I) lethal clusters. There is substantial alignment of the α2(I) lethal clusters and the proteoglycan binding sites on the fibril.

Figure 3. Electrophoretic analysis of type I collagen synthesized by dermal fibroblasts with mutations in genes coding for collagen 3-hydroxylation complex components

Most mutations in CRTAP, LEPRE1 or PPIB cause decreased or absent protein due to nonsense mediated decay. Both [H]-proline-labelled collagen alpha chains are fully overmodified in media and cell layer from primary fibroblast cultures of OI patients with CRTAP or LEPRE1 null mutations, indicating delayed folding of the collagen helix. However, in the fibroblasts of siblings with a mutated PPIB start codon, the secreted α chains have normal electrophoretic migration and collagen in the cell layer fraction has minimal backstreaking of α1(I).

Figure 4. Relationship between dominant and recessive forms of OI

Boxes in the left and right columns identify features of dominant and recessive OI, respectively. The central column of boxes list mechanisms which may be shared by both sets of mutations.