title: Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH.
abstract: Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I α1 mRNA and receptor activator of NF-κB ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Saini
authors.forename: Dean A
authors.initials: DA
authors.lastname: Marengi
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barry
authors.forename: Keertik S
authors.initials: KS
authors.lastname: Fulzele
authors.forename: Erica
authors.initials: E
authors.lastname: Heiden
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.forename: Christopher
authors.initials: C
authors.lastname: Dedic
authors.forename: Akira
authors.initials: A
authors.lastname: Maeda
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.forename: Paola Divieti
authors.initials: PD
authors.lastname: Pajevic
mesh_terms: D000818:Animals; D001835:Body Weight; D015519:Bone Density; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D053245:RANK Ligand; D044168:Receptor, Parathyroid Hormone, Type 1; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse
keywords: Anabolic; Bone; Catabolic; Mouse Genetics; Osteocyte; Osteoporosis; Parathyroid Hormone