title: Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis.
abstract: The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level.
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: Takao
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishimori
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Karaplis
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Endocrine Unit (T.H., T.K., S.N., H.M.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sir Mortimer B. Davis Jewish General Hospital (A.C.K.), McGill University, Montreal, Québec, Canada H3T 1E2; and Royal Victoria Hospital of the McGill University Health Centre (D.G.), Montreal, Québec, Canada H3A 1A1.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D004622:Embryo, Mammalian; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000235:genetics / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology
chemical_list: D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D002118:Calcium