Skeletal resistance to 1,25-dihydroxyvitamin D-3 in osteopetrotic rats

The osteopetrotic (op/op) rat mutation is a lethal mutation in which decrea sed osteoclast function (bone resorption) coexists with markedly elevated s erum levels of 1,25-dihydroxyvitamin D-3[1,25(OH)(2)D-3]. Increased circula ting levels of 1,25(OH)(2)D-3 have been reported in other osteopetrotic ani mal mutations and in some osteopetrotic children. This study examined the e ffects of 1,25(OH)(2)D-3 infusions on serum and skeletal parameters in norm al and mutant rats of op stock. We also examined vitamin D receptor express ion 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 minipump s implanted subcutaneously for 1 wk, Sera were analyzed for calcium, phosph orus, and 1,25(OH)(2)D-3 levels. Histomorphometric analyses of proximal tib iae from treated normal (50 ng/d) and op mutant (125 ng/d) rats and their v ehicle-infused controls were performed. Normal animals infused with 1,25(OH )(2)D-3 exhibited a dose-dependent increase in serum calcium levels. Histom orphometric analyses of metaphyseal bone within the primary spongiosae regi on 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 decre ase 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 cart ilage and metaphyseal bone compared with mutant controls. Vitamin D mRNA an d 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 it s receptor was similar between op mutant and normal animals. High dose calc itriol therapy, under the conditions and period of treatment used in this s tudy, failed to stimulate bone turnover in op rats, suggesting that they ar e resistant to the skeletal effects of 1,25(OH)(2)D-3. The failure of osteo clast activation in response to 1,25(OH)(2)D-3 treatment may be associated with osteoblast incompetence in this mutation.