Long-term administration of vitamin D3 metabolites alters PTH-responsive osteoblastic adenylate cyclase in rats

Summary We have examined the effect of induced hyper D₃ vitaminosis on bone-related variables in the rat with special reference to the parathyroid (PTH)-sensitive adenylate cyclase (AC) in rat calvariae. Subcutaneous injections three times a week of doses theoretically corresponding to about 10 times the average physiological serum levels of either 25 hydroxyvitamin D₃ (25OHD₃), 1,25 dihydroxyvitamin D₃ (1,25(OH)₂D₃), or 24,25 dihydroxyvitamin D₃ (24,25(OH)₂D₃) for 12 weeks gave the following results: At 12 weeks of treatment, 24,25(OH)₂D₃ levels in the groups receiving 25OHD₃ or 24,25(OH)₂D₃ increased significantly, whereas 1,25(OH)₂D₃ levels remained unaffected. Correspondingly, PTH-sensitive AC activities in crude calvarial membrane fractions from 25OHD₃-and 24,25(OH)₂D₃-treated animals were obliterated. This effect was apparent after 4 weeks of treatment. In the group receiving 25OHD₃, both basal, plus Gpp(NH)p-, and forskolin-sensitive AC activities were significantly reduced after 4 weeks of treatment. Similar effects in crude kidney membrane fractions were, however, not observed. Liver membranes from 25OHD₃- or 24,25(OH)₂D₃-treated animals showed insignificant changes in the isoprenalin-, PGE₁-, Gpp(NH)p-, or forskolin-sensitive AC activities. Finally, the significance of reduced PTH-sensitive bone AC activity has been assessed. 25OHD₃ treatment yielded normocalcemic and hypercalciuric rats, whereas 1,25(OH)₂D₃ enhanced both serum and urine Ca²⁺ levels. 24,25(OH)₂D₃-treated and control animals were undiscernible in this respect. However, the 24,25-(OH)₂D₃ treatment caused reductions in both serum alkaline phosphatase levels and urinary hydroxyproline/creatinine ratio. These results indicate that administration of vitamin D₃ metabolites which increase serum 24,25(OH)₂D₃ levels without affecting renal handling of Ca²⁺, obliterates the PTH-sensitive AC in bone, thereby altering bone turnover.