Bone and Extracellular Matrix Branch

Joan C. Marini, MD, PhD, Chief

This year, the Bone and Extracellular Matrix Branch (BEMB) focused on leading the Consortium for Mutations in Osteogenesis Imperfecta (OI). This international consortium of eight laboratories has pooled the OI mutations identified by the respective laboratories, resulting in a landmark review of over 800 mutations. In addition to the value of the compendium itself, the results of genotype-phenotype modeling have provided testable models for the mechanism of the lethal forms of the bone dysplasia. Two regions in the carboxyl half of the a1(I) chain, which exclusively contain lethal mutations, align with the Major Ligand Binding Regions (MLBR) II and III. These regions contain the sites for binding between type I collagen triple helices and multiple ligands, including integrins and fibronectin. The Consortium database supports the Regional Model, previously proposed by members of the Branch, for lethal mutations in the a2(I) chain. In this chain, lethal mutations occur in eight clusters that are regularly spaced along the chain and coincide with the binding sites of the collagen fibril for matrix proteoglycans.

The BEMB has also continued to investigate the mechanism of OI/EDS (Ehlers-Danlos syndrome), which is caused by mutations in the anchor region at the amino end of the α1(I) collagen chain. Glycine substitutions in this region destabilize the anchor domain and unfold the adjacent N-proteinase cleavage site, interfering with procollagen processing. The resultant pN-collagen is incorporated into matrix, yielding dramatically thinner fibrils. Thus, the defects in OI/EDS have a dual function: they cause osteoporosis directly by altering bone matrix structure and EDS indirectly by interfering with collagen processing.

Detailed investigation of the biochemical assay commonly used for diagnosis of OI has shown that the diagnosis has variable sensitivity for glycine substitutions located in the amino end of the chains. Complete diagnosis of substitutions in the amino third of α1(I) and amino half of α2(I) requires supplementation with sequencing.

The BEMB's clinical investigations continue to play an important role in the treatment of OI. Previously, controlled trials with the bisphosphonate pamidronate distinguished the beneficial and detrimental aspects of such compounds in Brtl mice and children with OI. In children with types III and IV OI, treated patients experienced a significant increase in vertebral BMD z-scores, mid-vertebral height, and vertebral area. However, the increases in BMD tapered off after one to two years of treatment. Furthermore, treated patients did not experience positive functional effects in ambulation level, lower-extremity strength, or pain amelioration. The changes previously reported in these parameters in uncontrolled trials appear to have been placebo effects. The BEBM is currently engaged in a dose comparison trial based on the hypothesis that a reduced cumulative dose of bisphosphonate can result in the same improvements as those associated with the higher dose with decreased detrimental effects.