Skeletal resistance to 1,25-dihydroxyvitamin D3 in osteopetrotic rats

The osteopetrotic (op/op) rat mutation is a lethal mutation in which decreased osteoclast function (bone resorption) coexists with markedly elevated serum levels of 1,25-dihydroxyvitamin D-3[1,25(OH)(2)D-3]. Increased circulating levels of 1,25(OH)(2)D-3 have been reported in other osteopetrotic animal mutations and in some osteopetrotic children. This study examined the effects of 1,25(OH)(2)D-3 infusions on serum and skeletal parameters in normal and mutant rats of op stock. We also examined vitamin D receptor expression and binding in bone cells from op normal and mutant animals. Four-week-old normal and mutant rats were infused either with propylene glycol (used as controls) or with 12.5-125 ng of 1,25(OH)(2)D-3/d using osmotic minipumps implanted subcutaneously for 1 wk, Sera were analyzed for calcium, phosphorus, and 1,25(OH)(2)D-3 levels. Histomorphometric analyses of proximal tibiae from treated normal (50 ng/d) and op mutant (125 ng/d) rats and their vehicle-infused controls were performed. Normal animals infused with 1,25(OH)(2)D-3 exhibited a dose-dependent increase in serum calcium levels. Histomorphometric analyses of metaphyseal bone within the primary spongiosae region showed that 1,25(OH)(2)D-3 increased osteoclast number with a reduction in osteoblast surface associated with a decrease in growth plate cartilage thickness. However, similar analyses on secondary spongiosae showed a decrease in osteoclast number and surface associated with an anabolic response. Op mutants infused with 1,25(OH)(2)D-3 did not exhibit any change in serum calcium levels or histomorphometric parameters related to growth plate cartilage and metaphyseal bone compared with mutant controls. Vitamin D mRNA and protein levels were increased two- to threefold in op mutants compared to age-matched normal rats. However, binding affinity of 1,25(OH)(2)D-3 to its receptor was similar between op mutant and normal animals. High dose calcitriol therapy, under the conditions and period of treatment used in this study, failed to stimulate bone turnover in op rats, suggesting that they are resistant to the skeletal effects of 1,25(OH)(2)D-3. The failure of osteoclast activation in response to 1,25(OH)(2)D-3 treatment may be associated with osteoblast incompetence in this mutation.