Cooperative Roles Of Parathyroid Hormone And Calcium On Bone Formation Mediated Thgrough Calcium Sensing Receptor

To determine whether parathyroid hormone(PTH)and calcium(Ca) interact in neonatal bone formation,male PTH^-/-and female PTH^+/-or male PTH^+/-and female PTH^-/-mice were mated to generate PTH^+/-and PTH^-/-pups.PTH^+/-and PTH^-/-dames were fed either a normal(1%Ca, 0.6%P)or a high Ca(2%Ca and 0.4%P)diet.Dietary effects on milk content of minerals and calcium-regulating hormones were determined in dames,and the effects of milk content were assessed on bone turnover in 3-week-old PTH deficient pups.Milk Ca and 1,25(OH)₂D₃ levels were reduced,but milk PTH related peptide(PTHrP)levels were raised in the PTH^-/-dames compared to the PTH^+/-dames.Milk Ca levels were raised,but milk 1,25(OH)₂D₃ and PTHrP levels were decreased in both PTH^+/-and PTH^-/-dames fed the high Ca diet.Serum Ca levels were decreased and serum phosphorus levels were raised in the PTH^-/-pups fed by dames on the normal diet. Serum Ca and phosphorus levels were normalized and serum 1,25(OH)₂D₃ levels were decreased in the PTH^-/-pups fed by dames on the high Ca diet.Bone mineral density(BMD),trabecular volume (BV/TV)and the number of osteoblasts were reduced significantly in the PTH^-/-pups compared to the PTH^+/-pups.BMD,BV/TV and the number of osteoblasts were also reduced in both PTH^+/-and PTH^-/-pups fed by PTH^-/-dames compared to pups fed by PTH^+/-dames on normal diets.In contrast,BMD and BV/TV were increased significantly,in both PTH^+/- and PTH^-/-pups fed by dames on a high Ca diet.Bone formation parameters were highest in the PTH^+/-pups fed by the PTH^+/-dames on the high Ca 1 diet,and lowest in the PTH^-/-pups fed by the PTH^-/-dames on the normal diet.These results indicate that PTH deficiency results in a decrease in osteoblastic bone formation and this decrease can be partly but not completely rescued by a high Ca 1 diet.Consequently,PTH and calcium each has skeletal anabolic action and play a cooperative role on osteoblastic bone formation in the neonate.to determine whether the cooperative roles of PTH and calcium on osteoblastic bone formation are mediated through calcium sensing receptor(CaSR),we created a PTH and CaSR double gene knockout (PTH^-/-CaSR^-/-)animal models.PTH^+/-CaSR^+/-dames were fed either the normal or the high Ca diet.The skeletal Phenotypes of PTH^-/-CaSR^-/-pups were compared to PTH^-/-and wild-type pups at 3-weeks of ages by histology,histomorphormatric analysis and real-time RT-PCR for typeâ… collagen.The results showed that trabecular bone volume,osteoblast number and typeâ… collagen gene expression were reduced significantly in PTH^-/- pups compared to WT pups and were decreased dramatically in PTH^-/-CaSR^-/-pups compared to WT and PTH^-/-pups fed by dames on either normal diet or the high Ca diet.These bone formation parameters were increased in WT and PTH^-/-pups,but not in PTH^-/-CaSR^-/-pups fed by dames on the high Ca diet compared to the pups fed by dames on the normal diet.There results indicate that CaSR mediates bone anabolic actions of both PTH and calcium.Our results imply that dietary calcium supplementation during pregnancy and lactation playas benefits on neonatal skeletal development and growth.This study provides a experimental and theoretical evidence for the combination of PTH with calcium to treat osteoporosis.