bone and extracellular
matrix branch
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Joan C. Marini, MD,
PhD, Chief The Bone and Extracellular Matrix Branch
(BEMB) conducts research on the extracellular matrix of bone and on diseases
resulting from defective matrix. The Section on Heritable Bone
Disorders, led by Joan 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.
Mutations at both the amino and carboxyl ends of the collagen molecule have
been a primary research focus. At the amino end of the helical region of the
alpha1(I) chain, the group identified a set of mutations that delineate a
distinct folding region and cause a combination of the symptoms of OI and
Ehlers-Danlos syndrome (EDS). Mutations in the first 90 residues destabilize
the anchoring function of the end of the helix and unfold the secondary
structure of 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, causing osteoporosis directly
by altering bone matrix structure and EDS indirectly by interfering with
procollagen processing. The mechanism of EDS is shared with EDS VII patients,
with abnormal processing attributable to absence of the N-proteinase cleavage
site from collagen chains. The section has also undertaken investigations at
the carboxyl end of the procollagen chains and has identified five novel
mutations in patients with types II (lethal), III (severe), and IV (moderate)
OI. The mutations all delay incorporation of the mutant chains into the
procollagen helix. Interestingly, the portion of the procollagen molecule
containing the 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 the mutations must differ from those
in the collagen helix. Studies are currently centering on the
mutations’ intracellular behavior and matrix biology. The effects of bisphosphonate
drugs on OI bone have been evaluated in both the Brtl mouse model for OI
generated by this section and in the pediatric OI population. In the mouse,
bisphosphonate increased femoral bone volume and the load at which Brtl and
wild-type femurs fracture, but with a negative impact on bone quality, namely,
a decrease in bone strength and increase in brittleness, persistence of
mineralized cartilage resulting in higher fracture risk, and an apparent
toxic effect on the morphology of Brtl osteoblasts. In the randomized
controlled trial of pamidronate in children with types III and IV OI, which
the section conducted, treated patients experienced a significant increase in
vertebral BMD z-scores and an increase in L1-L4 mid-vertebral height and
total vertebral area compared with untreated patients. However, the 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. |