Our hypothesis is that in certain individuals and kindreds, adult-onset osteoporosis primarily results from an inherited disorder of Type I collagen synthesis. Previous studies have suggested the existence of defective synthesis of Type I collagen in postmenopausal osteoporosis. Twin studies indicate that heredity as well as environmental factors play a role in determining skeletal mass. Mother/daughter association and familial clustering of osteoporosis are not at all uncommon. Based on our past observation that pedigree of osteogenesis imperfecta exhibit great heterogenity in the severity of osteopenia, we believe it is appropriate to explore the relationship of heredity and collagen synthesis in osteoporotic subjects whose pedigree reveals a family history of postmenopausal osteoporosis and other mild connective tissue abnormalities. Ten osteoporotic peri- and postmenopausal probands whose relatives also have stigmata of a connective tissue lesion will be studied. Adult familial osteoporosis is thus defined as the familial occurrence of fractures during mid-or late adult life, short stature, scoliolis and/or hyperectensible joints. Following identification of the proband, we will measure Types I and III collagen synthesis by dermal fibroblasts, the ratios of alpha chains for these collagen types and the levels of mRNA for Type I and III collagens. Once a potential abnormality in Type I collagen is identified in the proband, then other family members will be studied both biochemically and clinically to determine if the putative marker segregates with clinical stigmata in the family. Linkage polymorphisms for the alpha-2 chain of Type I collagen will be sought within affected kindreds. The clinical features of familial osteoporosis will be defined by the measurement of vertebral bone mineral content by computer tomographic scan (QCT). The metabolic activity of bone will be assessed by histomorphometric analysis of iliac crest biopsies, determination of serum osteocalcin and osteonectin levels, urinary Gla protein excretion and the urinary excretion of hydroxyproline. By selecting the appropriate probands and family controls this study may define an important subset of the osteoporotic population, whose disease can be defined by distinct biochemical and clinical criteria. Analysis of the hereditary nature and putative gene defect of this subgroup will form the basis for the investigation of molecular lesions affecting skeletal tissues in other osteoporotic women.
| Chipman, S D; Sweet, H O; McBride Jr, D J et al. (1993) Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci U S A 90:1701-5 |
| Shapiro, J R; Stover, M L; Burn, V E et al. (1992) An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen. J Clin Invest 89:567-73 |
