title: Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes.
abstract: The therapeutic goal of increasing bone mass by co-treatment of parathyroid hormone (PTH) and an osteoclast inhibitor has been complicated by the undefined contribution of osteoclasts to the anabolic activity of PTH. To determine whether active osteoclasts are required at the time of PTH administration, we administered a low dose of the transient osteoclast inhibitor salmon calcitonin (sCT) to young rats receiving an anabolic PTH regimen. Co-administration of sCT significantly blunted the anabolic effect of PTH as measured by peripheral quantitative computer tomography (pQCT) and histomorphometry in the femur and tibia, respectively. To determine gene targets of sCT, we carried out quantitative real time PCR and microarray analysis of metaphyseal samples 1.5, 4 and 6.5h after administration of a single injection of PTH, sCT or PTH+sCT. Known targets of PTH action, IL-6, ephrinB2 and RANKL, were not modified by co-administration with sCT. Surprisingly, at all time points, we noted a significant upregulation of sclerostin mRNA by sCT treatment, as well as down-regulation of two other osteocyte gene products, MEPE and DMP1. Immunohistochemistry confirmed that sCT administration increased the percentage of osteocytes expressing sclerostin, suggesting a mechanism by which sCT reduced the anabolic effect of PTH. Neither mRNA for CT receptor (Calcr) nor labeled CT binding could be detected in sclerostin-enriched cells differentiated from primary calvarial osteoblasts. In contrast, osteocytes freshly isolated from calvariae expressed a high level of Calcr mRNA. Furthermore immunohistochemistry revealed co-localization of CT receptor (CTR) and sclerostin in some osteocytes in calvarial sections. Taken together these data indicate that co-treatment with sCT can blunt the anabolic effect of PTH and this may involve direct stimulation of sclerostin production by osteocytes. These data directly implicate calcitonin as a negative regulator of bone formation through a previously unsuspected mechanism.
authors.affiliation: Department of Medicine at St. Vincent's Hospital, St. Vincent's Institute and University of Melbourne, Fitzroy, 3065, Australia.
authors.forename: J H
authors.initials: JH
authors.lastname: Gooi
authors.forename: S
authors.initials: S
authors.lastname: Pompolo
authors.forename: M A
authors.initials: MA
authors.lastname: Karsdal
authors.forename: N H
authors.initials: NH
authors.lastname: Kulkarni
authors.forename: I
authors.initials: I
authors.lastname: Kalajzic
authors.forename: S H M
authors.initials: SH
authors.lastname: McAhren
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.forename: J E
authors.initials: JE
authors.lastname: Onyia
authors.forename: P W M
authors.initials: PW
authors.lastname: Ho
authors.forename: M T
authors.initials: MT
authors.lastname: Gillespie
authors.forename: N C
authors.initials: NC
authors.lastname: Walsh
authors.forename: L Y
authors.initials: LY
authors.lastname: Chia
authors.forename: J M W
authors.initials: JM
authors.lastname: Quinn
authors.forename: T J
authors.initials: TJ
authors.lastname: Martin
authors.forename: N A
authors.initials: NA
authors.lastname: Sims
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002116:Calcitonin / Q000494:pharmacology*; D002478:Cells, Cultured; D019295:Computational Biology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013977:Tibia / Q000187:drug effects / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D015850:Interleukin-6; D010281:Parathyroid Hormone; D010750:Phosphoproteins; C486031:Sost protein, rat; C028815:salmon calcitonin; D002116:Calcitonin