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Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
Address all correspondence and requests for reprints to: L. Darryl Quarles, M.D., Box 3036, Duke University Medical Center, Durham, North Carolina 27710. E-mail: quarl001{at}mc.duke.edu
The hypothesis that local changes in extracellular calcium may serve a physiological role in regulating osteoblast, osteoclast, and cartilage function through the extracellular cation-sensing receptor, CasR, is gaining widespread support, but lacks definite proof. To examine the effects of CasR deficiency 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 hyperparathyroidism, hypercalcemia, and hypophosphatemia. Except for dwarfism, the expected skeletal manifestations of PTH excess, namely chondrodysplasia and increased mineralized bone formation and resorption, were not the main skeletal features in CasR-/- mice. Rather, rickets was the predominant skeletal abnormality in these animals, as evidenced by a widened zone of hypertrophic chondrocytes, impaired growth plate calcification and disorderly deposition of mineral, excessive osteoid accumulation, and prolonged mineralization lag time in metaphyseal bone. CasR transcripts were identified in cartilage and bone marrow of CasR+/+ mice, but not in mineralized bone containing mature osteoblasts and osteocytes. These findings indicate that a calcium-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.
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