Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH

• Published in: The Journal of biological chemistry 2013-07, Vol.288 (28), p.20122-20134
• Main Authors: Saini, Vaibhav, Marengi, Dean A., Barry, Kevin J., Fulzele, Keertik S., Heiden, Erica, Liu, Xiaolong, Dedic, Christopher, Maeda, Akira, Lotinun, Sutada, Baron, Roland, Pajevic, Paola Divieti
• Format: Article
• Language: English
• Subjects: Anabolic; Animals; Body Weight; Bone; Bone and Bones - cytology; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density; Catabolic; Cells, Cultured; Collagen Type I - genetics; Collagen Type I - metabolism; Female; Gene Expression; Immunohistochemistry; In Situ Hybridization; Male; Mice; Molecular Bases of Disease; Mouse Genetics; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteocyte; Osteocytes - drug effects; Osteocytes - metabolism; Osteoporosis; Osteoprotegerin - genetics; Osteoprotegerin - metabolism; Parathyroid Hormone; Parathyroid Hormone - pharmacology; RANK Ligand - genetics; RANK Ligand - metabolism; Receptor, Parathyroid Hormone, Type 1 - genetics; Receptor, Parathyroid Hormone, Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.441360

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. Background: Osteocytes, the most abundant cells in adult bone, express PPR. Results: Mice with constitutive PPR deletion in osteocytes demonstrate blunted anabolic and catabolic bone responses and the inability to recruit osteoblasts and osteoclasts upon PTH administration. Conclusion: PPR in osteocytes is needed for a full skeletal response to PTH administration. Significance: PPR signaling in osteocytes is necessary for PTH-driven anabolic effects during osteoporosis therapy.