The Extracellular Calcium-Sensing Receptor (CaSR) Is a Critical Modulator of Skeletal Development

Abstract

The extracellular Ca2+-sensing receptor (CaSR) plays a nonredundant role in the functions of the parathyroid gland (PTG) and the kidney. Severe hyperparathyroidism, premature death, and incomplete gene excision in Casr−/− mice have precluded the assessment of CaSR function in other tissues. We generated mice with tissue-specific deletion of Casr in the PTG, bone, or cartilage. Deletion of Casr in the PTG or bone resulted in profound bone defects, whereas deletion of Casr in chondrocytes (cartilage-producing cells) resulted in death before embryonic day 13 (E13). Mice in which chondrocyte-specific deletion of Casr was induced between E16 and E18 were viable but showed delayed growth plate development. Our data show a critical role for the CaSR in early embryogenesis and skeletal development.

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

“…[Ca 2þ ] e and the CaSR, however, have been reported to modulate growth plate chondrocyte differentiation in vitro, (21)(22)(23) and targeted deletion of the CaSR from chondrocytes has been reported to be lethal in utero before embryonic day 13 but to produce viable mice with delayed growth plate development if conditional targeted deletion in these cells is induced between E16 and E18. (12) In our studies, mutant mice deficient in both the CaSR and the 1a(OH)ase enzyme grew extremely poorly on the normal calcium intake and were significantly smaller than those deficient in only vitamin D. This reduction in growth was associated with major abnormalities of the growth plate, including widening and disorganization of the cellular progression from proliferative to hypertrophic zones observed in wildtype mice and with less mineral deposition at the chondroosseous junction than was seen even in the single-mutant 1a(OH)ase À/À mice. The reduced mineralization may have been secondary at least in part to the more severe hypophosphatemia observed in the double mutants, (24) who had more severe hyperparathyroidism.…”

“…The contribution of hyperparathyroidism similarly may explain, at least in part, the mineralization defect previously reported in mice with parathyroid-specific CaSR deletion. (12) In Casr À/À 1a(OH)ase À/À mice on a rescue diet, however, PTH levels in the circulation remained high, and osteoblast numbers and activity remained elevated, resulting in persistently increased trabecular bone volume. Despite this evidence of persistently augmented bone matrix synthesis, osteoid volume was reduced, and the MAR and BMD were improved in the presence of ambient hypercalcemia, even in the face of hypophosphatemia.…”

“…Recent in vivo studies have shown that transgenic mice with a constitutively active mutant CaSR targeted to mature osteoblasts demonstrated enhanced bone resorption, (11) whereas mice with osteoblast-specific deletion exhibited severely undermineralized skeletons. (12) Mice with chondrocyte-specific deletion of Casr displayed delayed growth plate development. (12) The early lethality in the neonatal period of mice with homozygous Casr deletion (Casr À/À ) (4) precludes assessment of the progression of skeletal abnormalities in this model.…”

“…(12) Mice with chondrocyte-specific deletion of Casr displayed delayed growth plate development. (12) The early lethality in the neonatal period of mice with homozygous Casr deletion (Casr À/À ) (4) precludes assessment of the progression of skeletal abnormalities in this model. This early lethality is, however, corrected by crossing these mice with mice that manifest hypoparathyroidism, suggesting that the early lethality could be corrected by eliminating the hypercalcemia and hyperparathyroidism.…”

Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology

“…This is difficult to understand because the effect of even large variations in calcium intake levels on extracellular calcium concentrations [Ca 2 þ ] o is attenuated (Dvorak et al, 2004;Brown and Lian, 2008;Chang et al, 2008), as well as in limitation of cellular growth of normal and neoplastic cells (Rodland, 2004). Conversely, low dietary calcium causes hyperparathyroidism by impairment of CaR activity and, by the same token, can be linked to the development of osteoporosis and of various malignancies.…”