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Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta
Insights
Osteogenesis imperfecta patients may have defective type I procollagen secretion. Fibroblasts from one lethal form patient produced abnormal procollagen chains, leading to reduced extracellular matrix components.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders characterized by bone fragility.
- OI exhibits significant clinical and genetic heterogeneity.
- The predominant feature of OI is bone fragility.
Purpose of the Study:
- To investigate the molecular mechanisms underlying a lethal perinatal form of osteogenesis imperfecta.
- To determine the cause of reduced type I procollagen in affected fibroblasts.
- To explore the role of collagen secretion in OI pathogenesis.
Main Methods:
- Cultured dermal fibroblasts from an OI patient were analyzed.
- Short-term labeling experiments were performed.
- Cells were treated with alpha,alpha'-dipyridyl to assess collagen hydroxylation.
- Cyanogen bromide peptide analysis was used to examine procollagen structure.
Main Results:
- Fibroblasts from the lethal perinatal OI patient secreted type I procollagen at half the normal rate.
- Two distinct pro alpha 1(I) chains were synthesized at equal rates.
- Analysis revealed structural differences in the primary structures of the two pro alpha 1(I) chains.
- Abnormal type I procollagen structure impaired normal secretion, leading to an altered ratio of type I procollagen to other extracellular matrix molecules.
Conclusions:
- Structural abnormalities in type I procollagen are implicated in the pathogenesis of at least one form of lethal perinatal osteogenesis imperfecta.
- Decreased secretion of structurally abnormal type I procollagen is a proposed mechanism for this OI subtype.
- Further research is needed to understand the full heterogeneity of OI and its underlying molecular defects.
Abstract:
Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connective tissue disorders in which bone fragility is the predominant feature. Cultured dermal fibroblasts from one patient with the lethal perinatal form of osteogenesis imperfecta secrete type I procollagen at a rate half that of normal cells. Short-term labeling experiments and treatment with alpha,alpha'-dipyridyl (which prevents posttranslational prolyl and lysyl hydroxylation) demonstrated that these cells produce two distinct pro alpha 1(I) chains, which are synthesized at the same rate. Analysis of cyanogen bromide peptides indicated that the two chains differ in their primary structures. Thus, structural abnormalities in type I procollagen prevent this molecule from being secreted normally, resulting in an anomalously low ratio of type I procollagen to other extracellular matrix molecules. While the lethal perinatal form of osteogenesis imperfecta may be heterogeneous, we propose that the underlying pathogenesis of at least one form is decreased secretion of type I procollagen.