Joan C. Marini, MD, PhD, Chief

The Bone and Extracellular Matrix Branch (BEMB) conducts research on the extracellular matrix of bone and diseases resulting from defective matrix. The Section on Heritable Bone Disorders, led by Joan C. Marini, undertakes an integrated program of laboratory and clinical research, focusing on osteogenesis imperfecta (OI) as a model disorder of extracellular matrix resulting in severe osteoporosis. Mutations at both the amino and carboxyl ends of the collagen molecule have been a primary interest. Members of the Section delineated a distinct folding region at the amino end of the alpha1(I)-helical region in which mutations cause a combination of the symptoms of OI and Ehlers-Danlos syndrome (EDS). Mutations in the first 90 residues destabilize the anchoring domain and unfold the adjacent N-proteinase cleavage site. As a result, the procollagen cannot be processed at the amino end and pN-collagen is incorporated into matrix. In vivo, the pN-collagen causes strikingly decreased diameter of dermal fibrils. 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. Members of the Section are currently exploring the folding of the anchor region and the retention of the N-propeptide in fibrils. They have also been investigating the carboxyl end of the procollagen chains, where they have identified five 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, implying that the mechanism of these mutations must differ from those in the collagen helix. Pericellular processing as well as in vitro digestion with C-proteinase indicates delay in processing of the propeptide.

The Section has played an important role in OI treatment by conducting controlled trials of bisphosphonate drugs in the Brtl mouse model for OI generated by this Section and in the pediatric OI population. The investigations distinguished the beneficial and detrimental aspects of the drugs on OI bone. In the mouse, increased femoral bone volume and load at fracture came at the expense of decreased bone quality. Bone material strength decreased, and the brittleness of Brtl bone was exacerbated. 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, treated patients versus controls experienced a significantly greater increase in vertebral BMD z-scores, L1-L4 mid-vertebral height, and total vertebral area. However, the increases in BMD tapered after one to two years of treatment. Furthermore, the treated patients did not experience positive functional effects on 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.