Reproduction is associated with a remarkable cycle of bone loss and recovery. Newborns depend on milk for all nutrients, including calcium. Supplying enough calcium for milk production requires the mobilization of skeletal calcium in the mother, and lactation is a period of rapid bone loss. After weaning, when milk production ceases, bone mass recovers completely, almost as rapidly as it was lost during lactation. Our prior studies have defined a previously unrecognized feedback loop between breast and bone during lactation. Suckling stimulates afferent nerves in the breast to signal the hypothalamus to inhibit GnRH secretion and stimulate prolactin release. The resulting low estrogen levels, in turn, accelerate bone resorption and cause bone loss. In addition, the lactating breast secretes PTHrP into the systemic circulation and milk. Our data demonstrate that circulating PTHrP also contributes to increased osteoclastic bone resorption and bone loss. During lactation, skeletal calcium is mobilized for the purposes of milk production. Therefore, it is intriguing that the breast expresses the calcium-sensing receptor (CaR) and becomes a calcium-sensing organ that adjusts both PTHrP secretion and calcium transport in response to changes in the extracellular calcium concentration. We believe that this allows the lactating mammary gland to monitor its supply of calcium and to adjust its calcium utilization and skeletal calcium release accordingly. If calcium delivery to the mammary gland falls, less calcium is transported into milk and more PTHrP is secreted to increase delivery of skeletal calcium. This feedback loop may be particularly important to protect the mother from hypocalcemia when dietary calcium supplies are limiting. We also present data suggesting that a wave of osteoclast apoptosis just after weaning leads to a sudden inhibition of bone resorption and triggers skeletal recovery after lactation. Our goal in the extension of this grant is to examine the mechanisms by which estrogen withdrawal and PTHrP excess interact at a skeletal level to cause an increase in bone resorption and bone loss during lactation. We will also explore if a reciprocal increase in estrogen levels and fall in PTHrP levels may act to inhibit bone resorption at weaning. Finally, our data suggest that the PTHrP found in milk may exert effects on neonatal bone metabolism. Because PTHrP levels in milk are regulated by calcium availability to the mammary gland, we hypothesize that alterations in milk PTHrP levels may be a mechanism by which maternal and neonatal calcium and bone metabolism are coordinated to respond to nutritional cues in concert. We offer three new specific aims. The first will test if PTHrP and estrogen withdrawal together, acting through stimulation of RANKL signaling, are sufficient to explain all bone loss during lactation. The second will determine if alterations in RANKL signaling, estrogen levels and PTHrP concentrations contribute to osteoclast apoptosis and the inhibition of bone resorption that leads to bone recovery after weaning.
The final aim will use genetic models to define the effects of milk PTHrP on neonatal bone and mineral metabolism. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077565-07
Application #
7503385
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2007-09-30
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
7
Fiscal Year
2008
Total Cost
$320,812
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ardeshirpour, Laleh; Dumitru, Cristina; Dann, Pamela et al. (2015) OPG Treatment Prevents Bone Loss During Lactation But Does Not Affect Milk Production or Maternal Calcium Metabolism. Endocrinology 156:2762-73
Wysolmerski, John J (2013) Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 54:230-6
Mamillapalli, Ramanaiah; VanHouten, Joshua; Dann, Pamela et al. (2013) Mammary-specific ablation of the calcium-sensing receptor during lactation alters maternal calcium metabolism, milk calcium transport, and neonatal calcium accrual. Endocrinology 154:3031-42
Vanhouten, Joshua N; Wysolmerski, John J (2013) The calcium-sensing receptor in the breast. Best Pract Res Clin Endocrinol Metab 27:403-14
Hiremath, Minoti; Wysolmerski, John (2013) Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development. J Mammary Gland Biol Neoplasia 18:171-7
Liu, X Sherry; Ardeshirpour, Laleh; VanHouten, Joshua N et al. (2012) Site-specific changes in bone microarchitecture, mineralization, and stiffness during lactation and after weaning in mice. J Bone Miner Res 27:865-75
Wysolmerski, John J (2012) Osteocytic osteolysis: time for a second look? Bonekey Rep 1:229
Wysolmerski, John J (2012) Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab 97:2947-56
Boras-Granic, Kata; VanHouten, Joshua; Hiremath, Minoti et al. (2011) Parathyroid hormone-related protein is not required for normal ductal or alveolar development in the post-natal mammary gland. PLoS One 6:e27278
Ardeshirpour, Laleh; Brian, Susan; Dann, Pamela et al. (2010) Increased PTHrP and decreased estrogens alter bone turnover but do not reproduce the full effects of lactation on the skeleton. Endocrinology 151:5591-601

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