Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.
Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.
Sabbagh
Yves
Y
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Carpenter
Thomas O
TO
Demay
Marie B
MB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D017674:Hypophosphatemia / Q000150:complications*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D012279:Rickets / Q000209:etiology* / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism
D010281:Parathyroid Hormone; D010710:Phosphates; D011506:Proteins; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse; D002118:Calcium