title: The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.
abstract: Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.
authors.affiliation: McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Camirand
authors.affiliation: McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Department of Oncology, McGill University, Montreal, Québec, Canada.
authors.forename: Ajay
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Biology, Université Sainte-Anne, Pointe-de-l'Eglise, Nova Scotia, Canada.
authors.forename: Mohammadi
authors.initials: M
authors.lastname: Kaouass
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Panda
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Karaplis
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D014893:Weightlessness / Q000009:adverse effects*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016326:Extracellular Matrix Proteins; D044162:Parathyroid Hormone-Related Protein; D011388:Prolactin