title: Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment.
abstract: The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1-34 (0, 10, 30, or 90 microg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10 microg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30 microg), but the anabolic effects of high-dose PTH (90 microg) were consistently and significantly suppressed by rapamycin ( approximately 4-36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Niziolek
authors.forename: S
authors.initials: S
authors.lastname: Murthy
authors.forename: S N
authors.initials: SN
authors.lastname: Ellis
authors.forename: K B
authors.initials: KB
authors.lastname: Sukhija
authors.forename: T A
authors.initials: TA
authors.lastname: Hornberger
authors.forename: C H
authors.initials: CH
authors.lastname: Turner
authors.forename: A G
authors.initials: AG
authors.lastname: Robling
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001862:Bone Resorption / Q000097:blood / Q000139:chemically induced; D002352:Carrier Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D010281:Parathyroid Hormone; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus