Heritable Disorders Of Connective Tissue

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The Bone and Extracellular Matrix Branch conducts research on the extracellular matrix of bone and on diseases resulting from defective matrix. The Section on Heritable Bone Disorders, led by Joan C. Marini, conducts an integrated program of laboratory and clinical research, focusing on osteogenesis imperfecta (OI) as a model disorder of extracellular matrix resulting in severe osteoporosis. They have shown that biochemical screening of type I collagen in osteogenesis imperfecta does not detect excess modification resulting from glycine substitutions at the amino ends of the alpha chains. Complete detection of substitutions in the amino third of the a1(I) and amino half of the a2(I) chain requires supplementation by sequencing (Cabral et al (2006) J Med Genet 43:685). Mutations at both the amino and carboxyl ends of the collagen molecule have been a primary research focus. At the amino end of the alpha1(I) helical region, they delineated distinct combined phenotype of OI and Ehlers Danlos Syndrome and showed that it was caused by mutations in a distinct 90-residue folding region. These mutations unfold the adjacent N-proteinase cleavage site and interfere with procollagen processing. Incorporation of pN-collageninto matrix results in fibrils with strikingly decreased diameter. Thus, the defects in OI/EDS collagen have a dual role - they cause osteoporosis directly by altering bone matrix structure and EDS indirectly by interfering with procollagen processing. (Cabral et al (2005) JBC 280:19259; Makareeva et al (2006) JBC 281:6463) The Section has also been investigating the carboxyl end of the procollagen chains, where they have identified 5 novel mutations in patients with types II (lethal), III (severe) and IV (moderate) OI. These mutations all delay incorporation of the mutant chains into the procollagen helix. Interestingly, the portion of the procollagen molecule containing these mutations is cleaved from the helix before fibril assembly. Therefore, the mutations per se are not expected to be present in tissue matrix. This implies that the mechanism of these mutations must differ from those in the collagen helix. Pericellular processing as well as collaborative in vitro digestion with C-proteinase (David Hulmes, Lyon, France) indicates delay in processing of the propeptide. The Section played an important role in OI treatment by conducting controlled trials of bisphosphonate drugs in both the Brtl mouse model for OI generated by this Section, and in the pediatric OI population. These investigations distinguished the beneficial and detrimental aspects of these compounds on OI bone. In the mouse, increased femoral bone volume and load at fracture came at the expense of decreased material strength and increased brittleness. Fracture risk was increased by persistence of mineralized cartilage rests and a toxic effect on the morphology of Brtl osteoblasts was noted. In the randomized controlled trial of pamidronate in children with types III and IV OI (Letocha et al (2005) JBMR 20:977), treated patients experienced a significant increase in vertebral BMD z-scores, increased L1-L4 mid-vertebral height and total vertebral area, compared to controls. However, the increases in BMD tapered after 1-2 years of treatment. Furthermore, treated patients did not experience positive functional effects in ambulation level, lower extremity strength or amelioration of pain. The changes previously reported in these parameters appear to have been placebo effects in uncontrolled trials. The Section is currently engaged in a dose comparison trial of pamidronate, to determine whether a lower dose of pamidronate in pediatric OI can deliver the beneficial effects with reduced side effects.