Rickets in cation-sensing receptor-deficient mice: An unexpected skeletal phenotype

The hypothesis that local changes in extracellular calcium may serve a phys iological role in regulating osteoblast, osteoclast, and cartilage function through the extracellular cation-sensing receptor, CasR, is gaining widesp read support, but lacks definite proof. To examine the effects of CasR defi ciency on the skeleton, we performed a detailed analysis of the skeleton in CasR knockout mice (CasR(-/-)) and wild-type littermates (CasR(+/+)). CasR ablation in the parathyroid glands of CasR(-/-) mice resulted in hyperpara thyroidism, hypercalcemia, and hypophosphatemia. Except for dwarfism, the e xpected skeletal manifestations of PTH excess, namely chondrodysplasia and increased mineralized bone formation and resorption, were not the main skel etal features in CasR(-/-) mice. Rather, rickets was the predominant skelet al abnormality in these animals, as evidenced by a widened zone of hypertro phic chondrocytes, impaired growth plate calcification and disorderly depos ition of mineral, excessive osteoid accumulation, and prolonged mineralizat ion lag time in metaphyseal bone. CasR transcripts were identified in carti lage and bone marrow of CasR(+/+) mice, but not in mineralized bone contain ing mature osteoblasts and osteocytes. These findings indicate that a calci um-sensing receptor is present in the skeleton, and its absence results in defective mineralization of cartilage and bone by mechanisms that remain to be elucidated.