title: Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses.
abstract: Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous, and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10 kb-Dmp1 promoter drives a tamoxifen-inducible Cre-recombinase were mated with animals in which exon 1 of PPR is flanked by lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPR(cKO) mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPR(cKO) mice. Reduction of trabeculae number and thickness was also detected by micro-computed tomography analysis whereas bone volume fraction (BV/TV%) was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPR(cKO) mice were subjected to a low-calcium diet to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPR(cKO) animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Thier 1101, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Powell
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barry
authors.forename: Irena
authors.initials: I
authors.lastname: Tulum
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Harris
authors.forename: F Richard
authors.initials: FR
authors.lastname: Bringhurst
authors.forename: Paola Divieti
authors.initials: PD
authors.lastname: Pajevic
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D002136:Calcium, Dietary; D006706:Homeostasis / Q000502:physiology*; D006962:Hyperparathyroidism, Secondary / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010011:Osteocytes / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002136:Calcium, Dietary; D044168:Receptor, Parathyroid Hormone, Type 1