Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation.
Large amounts of calcium are transferred to offspring by milk. This demand results in negative calcium balance in lactating mothers and is associated with rapid bone loss. The mechanisms of bone loss during lactation are only partly understood. Several studies have suggested that parathyroid hormone-related protein (PTHrP) might be secreted into the circulation by the lactating mammary gland and regulate bone turnover during lactation. Because mammary development fails in the absence of PTHrP, conventional PTHrP knockout mice cannot be used to address this possibility. To examine this hypothesis, we therefore used mice carrying a beta-lactoglobulin promoter-driven Cre transgene, one null PTHrP allele, and one floxed PTHrP allele. Expression of Cre specifically in mammary epithelial cells during late pregnancy and lactation resulted in efficient deletion of the PTHrP gene; mammary gland PTHrP mRNA and milk PTHrP protein were almost completely absent. Removal of PTHrP from the lactating mammary glands resulted in reductions in levels of circulating PTHrP and 1,25-dihydroxy vitamin D and urinary cAMP. In addition, bone turnover was reduced and bone loss during lactation was attenuated. We conclude that during lactation mammary epithelial cells are a source of circulating PTHrP that promotes bone loss by increasing rates of bone resorption.
Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
Joshua N
JN
VanHouten
Pamela
P
Dann
Andrew F
AF
Stewart
Christine J
CJ
Watson
Michael
M
Pollak
Andrew C
AC
Karaplis
John J
JJ
Wysolmerski
D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000209:etiology; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D019426:Integrases / Q000235:genetics; D007774:Lactation / Q000378:metabolism*; D007782:Lactoglobulins / Q000235:genetics; D008321:Mammary Glands, Animal / Q000737:chemistry*; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000097:blood / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014764:Viral Proteins / Q000235:genetics
D007782:Lactoglobulins; D044162:Parathyroid Hormone-Related Protein; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D002117:Calcitriol; D002118:Calcium