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.
Showing the most recent 10 out of 12 publications
