title: Normalization of mineral homeostasis after reversal of osteopetrosis.
abstract: Whether a radiographic and histologic cure of osteopetrosis includes normalization of mineral homeostasis remains unknown. Thus, we explored the extent of defective mineral metabolism in the microphthalmic (mi/mi) mouse before and after cure. Under basal conditions mi mutants exhibit normocalcemia, hypophosphatemia, and elevated renal 25-hydroxyvitamin D-1-hydroxylase activity. However, administration of PTHrP (3 micrograms/h x 24 h) further stimulated enzyme activity in mi mutants with active disease, to a level no different than that in treated normals. Serum phosphorus levels also declined in mi/mi mice following PTHrP, suggesting a normal renal response to this hormone. In contrast, failure to suppress enzyme function in mi/mi mice following prolonged calcitriol infusion indicates that the observed enhancement of 1,25-dihydroxyvitamin D production occurred secondary to autonomous parathyroid function and/or nonparathyroid hormone-related stimuli. Although an increased fractional excretion and decreased tubular reabsorption of phosphate were demonstrated in mi/mi mice, serum PTH levels were no different in mi mutants compared with normal littermates. Following skeletal cure, the mi/mi mice surprisingly display normal serum phosphorus levels and renal enzyme activity. Moreover, treatment restored normal responsiveness to calcitriol suppression and maintained normal PTHrP responsiveness of enzyme activity. These data indicate that the cure of osteopetrosis in the mi mutant is universal and includes normalization of serum phosphorus and renal 25-hydroxyvitamin D-1-hydroxylase. Furthermore, these data suggest that phosphate depletion of unknown origin is the likely cause of elevated enzyme activity in this murine osteopetrotic mutant.
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000097:blood*; D003131:Combined Modality Therapy; D004100:Dihydroxycholecalciferols / Q000378:metabolism; D004195:Disease Models, Animal; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008850:Microphthalmos / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010022:Osteopetrosis / Q000235:genetics / Q000628:therapy*; D010281:Parathyroid Hormone / Q000097:blood; D044162:Parathyroid Hormone-Related Protein; D010758:Phosphorus / Q000097:blood*; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014807:Vitamin D / Q000378:metabolism
chemical_list: D004100:Dihydroxycholecalciferols; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D014807:Vitamin D; D010758:Phosphorus; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium