title: PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP.
abstract: PTH and PTHrP both act in the regulation of fetal mineral metabolism. PTHrP regulates placental calcium transfer, fetal blood calcium, and differentiation of the cartilaginous growth plate into endochondral bone. PTH has been shown to influence fetal blood calcium, but its role in skeletal formation remains undefined. We compared skeletal morphology, mineralization characteristics, and gene expression in growth plates of fetal mice that lack parathyroids and PTH (Hoxa3 null) with the effects of loss of PTHrP (Pthrp null), loss of PTH/PTHrP receptor (Pthr1 null), and loss of both PTH and PTHrP (Hoxa3 null x Pthrp null). Loss of PTH alone does not affect morphology or gene expression in the skeletal growth plates, but skeletal mineralization and blood calcium are significantly reduced. In double-mutant fetuses (Hoxa3 null/Pthrp null), combined loss of PTH and PTHrP caused fetal growth restriction, limb shortening, greater reduction of fetal blood calcium, and reduced mineralization. These findings suggest that 1) PTH may play a more dominant role than PTHrP in regulating fetal blood calcium; 2) blood calcium and PTH levels are rate-limiting determinants of skeletal mineral accretion; and 3) lack of both PTH and PTHrP will cause fetal growth restriction.
authors.affiliation: Faculty of Medicine-Endocrinology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6. ckovacs@mun.ca
authors.forename: C S
authors.initials: CS
authors.lastname: Kovacs
authors.forename: L L
authors.initials: LL
authors.lastname: Chafe
authors.forename: N J
authors.initials: NJ
authors.lastname: Fudge
authors.forename: J K
authors.initials: JK
authors.lastname: Friel
authors.forename: N R
authors.initials: NR
authors.lastname: Manley
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001842:Bone and Bones / Q000196:embryology; D002118:Calcium / Q000097:blood*; D005312:Fetal Blood; D005317:Fetal Growth Retardation / Q000209:etiology; D005333:Fetus / Q000033:anatomy & histology / Q000378:metabolism; D015870:Gene Expression; D006132:Growth Plate / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010280:Parathyroid Glands / Q000002:abnormalities / Q000196:embryology; D010281:Parathyroid Hormone / Q000172:deficiency / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012863:Skeleton
chemical_list: D018398:Homeodomain Proteins; C080331:Hoxa3 protein, mouse; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D002118:Calcium