The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport
Joshua VanHouten, Pamela Dann, Grace McGeoch, Edward M. Brown, Karen Krapcho, Margaret Neville, John J. Wysolmerski
Joshua VanHouten, Pamela Dann, Grace McGeoch, Edward M. Brown, Karen Krapcho, Margaret Neville, John J. Wysolmerski
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Article Endocrinology

The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport

Abstract

The transfer of calcium from mother to milk during lactation is poorly understood. In this report, we demonstrate that parathyroid hormone–related protein (PTHrP) production and calcium transport in mammary epithelial cells are regulated by extracellular calcium acting through the calcium-sensing receptor (CaR). The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation. Increasing concentrations of calcium, neomycin, and a calcimimetic compound suppress PTHrP secretion by mammary epithelial cells in vitro, whereas in vivo, systemic hypocalcemia increases PTHrP production, an effect that can be prevented by treatment with a calcimimetic. Hypocalcemia also reduces overall milk production and calcium content, while increasing milk osmolality and protein concentrations. The changes in milk calcium content, milk osmolality, and milk protein concentration were mitigated by calcimimetic infusions. Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP. We conclude that the lactating mammary gland can sense calcium and adjusts its secretion of calcium, PTHrP, and perhaps water in response to changes in extracellular calcium concentration. We believe this defines a homeostatic system that helps to match milk production to the availability of calcium.

Authors

Joshua VanHouten, Pamela Dann, Grace McGeoch, Edward M. Brown, Karen Krapcho, Margaret Neville, John J. Wysolmerski

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Plasma calcium, PTH, and PTHrP levels, milk PTHrP concentrations, and PT...
Plasma calcium, PTH, and PTHrP levels, milk PTHrP concentrations, and PTHrP mRNA expression levels in lactating mice fed a normal calcium diet, a low calcium diet, or a low calcium diet and treated with either NPS S467 or NPS R467. (a) Plasma calcium concentrations in mice fed either a normal-calcium diet (0.6%) or a low-calcium diet (0.01%). Mice on a low-calcium diet either received nothing (low Ca) or were infused with NPS S467 at 40 μmol/kg/d or with NPS R467 at doses of 4 μmol/kg/d (low R467) or 40 μmol/kg/d (high R467). Calcium restriction led to a significant decline in plasma calcium (P < 0.001, normal Ca vs. low Ca). The higher dose of NPS R467 led to a further significant decline in plasma calcium (P < 0.01, low Ca vs. low Ca plus high R467). (b) Plasma PTH in mice on normal or low-calcium diets with or without calcimimetic treatment. (c) Milk PTHrP concentrations in the same groups described above. Milk PTHrP concentrations were significantly different in groups given low Ca (P < 0.05) and low Ca plus S467 (P < 0.05) compared with the group on a normal diet. However, milk PTHrP concentrations in the mice treated with NPS R467 were not significantly different from baseline. (d) PTHrP mRNA levels in mammary glands of mice on a normal-calcium diet (NC), a low-calcium diet (LC), a low-calcium diet with NPS S467 treatment (40 μmol/kg/d), or a low-calcium diet with NPS R467 treatment (40 μmol/kg/d) assessed by RNase protection analysis. Forty micrograms of total RNA was assayed. The bar graph represents cumulative data from four animals per treatment normalized to cyclophilin. (e) Circulating plasma PTHrP levels in mice fed a normal-calcium diet or a low-calcium diet.