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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Pup weight, milk protein concentration, and milk osmolality measured in ...
Pup weight, milk protein concentration, and milk osmolality measured in lactating dams receiving a normal calcium diet or in calcium-restricted lactating mice treated with a calcimimetic or the control compound. (a) Average pup body weight on day 12 of lactation in litters suckling on dams fed a normal-calcium diet or a low-calcium diet with or without calcimimetic treatment. Mice received 40 μmol/kg/d of NPS S467 or one of two doses of NPS R467, 4 μmol/kg/d (low) or 40 μmol/kg/d (high). Pups were significantly smaller when mothers consumed a low-calcium diet. Calcimimetic treatment did not significantly increase pup weight. (b) Protein concentration of milk derived from the groups of mice described in a. Each bar represents the mean of three to nine samples; error bars represent the SEM. Milk protein was significantly higher in samples from mice on a low-calcium diet compared with mice on a normal-calcium diet (P < 0.001) or mice receiving NPS R467 (P < 0.01). However, the protein concentrations were not significantly different in milk from mice receiving NPS R467 compared with milk from those on a normal diet. (c) Milk osmolality in samples from the same groups described in a and b. Osmolality was significantly increased in milk from calcium-restricted mice (P < 0.001 vs. normal Ca) and mice receiving NPS S467 (P < 0.01 vs. normal Ca). The low dose of NPS R467 did not significantly decrease milk osmolality, but the high dose did (P < 0.001 for low Ca vs. low Ca plus high R467). mOsm, milliosmoles.