Year: 2002
Type: article
Abstract: Osteogenesis imperfecta (OI) represents a phenotypically heterogeneous group of conditions that result from a number of genetic defects in the synthesis of type 1 collagen (1). The clinical expression is primarily that of bone fragility, but other tissues can also be involved, including teeth, ligaments, and joints. The clinical classification system devised by Sillence and colleagues (1) describes most cases of OI, but recent modifications to this system encompass additional forms of the disease. Phenotypes range from a mild form that may cause only a few childhood fractures with no deformity (type I) to the most severe form (type II), which is usually lethal in the perinatal period due to multiple fractures and marked bony deformities. Types III and IV are both associated with deformity and are the most difficult to manage clinically. Each phenotype results from one or more defects in collagen production, almost all inherited in an autosomal dominant fashion. At least 200 disease alleles have been reported in the COL1A1 or COL1A2 genes, and qualitative collagen defects are found to alter the structure of type 1 collagen in all forms of the disease (2). However, the milder and most commonly seen clinical variants of OI result from premature stop codons, or out-of-frame RNA splicing defects that lead to a reduction in the absolute level of type 1 collagen α-1 RNA. Recently, two variants of OI (labeled types V and VI), which involve mutations affecting genes other than those encoding type 1 collagen chains, have been described (3, 4).
The genetics of OI and the biochemical abnormalities of type 1 collagen associated with increased fracture risk have become increasingly well understood. However, the metabolic consequence of OI on the skeleton, as well as its contribution to fracture risk, still remains poorly characterized, in part because of the difficulty in evaluating skeletal homeostasis in children. For this reason, it was difficult to anticipate the effects of treating OI patients with pamidronate, an agent that has been employed as a means to reduce fractures and deformity (5, 6). Pamidronate would be expected to reduce bone remodeling but have no effect on collagen expression in OI patients or many of the immediate sequellae of incorporating mutant collagen chains into the bone matrix. Nevertheless, the elegant histomorphometric evaluations of iliac crest biopsies by Rauch et al. (7) in this issue of the JCI confirm the utility of this approach and begin to shed some light on the mechanisms by which pamidronate acts.
DOI: 10.1172/jci0217051
Author: Robert Lindsay
Institutions: Helen Hayes Hospital, Columbia University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1970109883