Skeletal development (bone modeling) is a precisely regulated coordination of bone formation and bone resorption. While the cellular and molecular bases for the coupling of these processes in the adult skeleton (bone remodeling) is becoming increasingly appreciated, bone modeling is understood poorly if at all. This proposal uses the congenital osteopetroses in mice, a disease of skeletal sclerosis characterized by reduced resorption, increased formation and delayed mineralization accompanied by elevations in blood levels of 1,25 dihydroxyvitamin D (1,25), to explore the role of vitamin D in bone modeling. These studies are expected to provide insights into the cellular control of skeletal mass and have application in situations where selectively activated bone formation may be desirable in skeletal development and maintenance.
Our specific aims are to characterize vitamin D metabolism and examine its regulation in three different osteopetrotic mutations in the mouse, to determine the interrelationships of these vitamin D abnormalities and the derangements in skeletal modeling and to explore vitamin D regulation in surgically and biochemically manipulated osteopetrotic and normal mice. Biochemical parameters of vitamin D metabolism in each mutation will be characterized by confirmation of our preliminary findings of elevated renal 1 OHase land depressed 24 OHase, examination of 1,25 turnover and delineation of the mineralization defects. One mouse mutation (mi) can be cured and the disease induced in normal littermates by reciprocal bone marrow transplantation. The changes in vitamin D metabolism, bone cell cytology, serum Ca and P and mineralization during cure and induction will be determined and compared. In the two other mutants (oc and op) which cannot be cured by bone marrow transplantation changes in vitamin D metabolism subsequent to spontaneous remission (op) or its absence (oc) will be explored. Future studies will be directed at delineation of the renal tubular defect, and development of strategies for the cure and induction of osteopetrosis in mice of oc and op stocks.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039737-03
Application #
3159958
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1991-02-01
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Nesbitt, T; Drezner, M K (1997) Phosphate transport in renal cell cultures of gy mice: evidence of a single defect in X-linked hypophosphatemia. Am J Physiol 273:F113-9
Nesbitt, T; Byun, J K; Drezner, M K (1996) Normal phosphate transport in cells from the S2 and S3 segments of Hyp-mouse proximal renal tubules. Endocrinology 137:943-8
Sundquist, K T; Cecchini, M G; Marks Jr, S C (1995) Colony-stimulating factor-1 injections improve but do not cure skeletal sclerosis in osteopetrotic (op) mice. Bone 16:39
Peura, S R; Marks Jr, S C (1995) Colony-stimulating factor 1 when combined with parathyroid hormone or 1,25-dihydroxyvitamin D can produce osteoclasts in cultured neonatal metatarsals from toothless (tl-osteopetrotic) rats. Bone 16:335S-340S
Nesbitt, T; Marks Jr, S C; Jackson, M E et al. (1995) Normalization of mineral homeostasis after reversal of osteopetrosis. J Bone Miner Res 10:1116-21
Nesbitt, T; Econs, M J; Byun, J K et al. (1995) Phosphate transport in immortalized cell cultures from the renal proximal tubule of normal and Hyp mice: evidence that the HYP gene locus product is an extrarenal factor. J Bone Miner Res 10:1327-33
Waud, C E; Marks Jr, S C; Lew, R et al. (1994) Bone mineral density in the femur and lumbar vertebrae decreases after twelve weeks of diabetes in spontaneously diabetic-prone BB/Worcester rats. Calcif Tissue Int 54:237-40
Bollerslev, J; Marks Jr, S C; Mosekilde, L et al. (1994) Cortical bone osteocalcin content and matrix composition in autosomal dominant osteopetrosis type I. Eur J Endocrinol 130:592-4
Nesbitt, T; Drezner, M K (1993) Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity. Endocrinology 132:133-8
Friedman, N E; Lobaugh, B; Drezner, M K (1993) Effects of calcitriol and phosphorus therapy on the growth of patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 76:839-44

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