title: Parathyroid hormone and prostaglandin E2 preferentially increase luciferase levels in bone of mice harboring a luciferase transgene controlled by elements of the pro-alpha1(I) collagen promoter.
abstract: Type I collagen is the major extracellular protein in bone, tendons, ligaments, and skin. DNA elements of the mouse pro-alpha1 (I) collagen promoter were shown to drive the bone-selective expression of a luciferase transgene. We examined whether this expression can be used to evaluate the effect of anabolic agents on bone formation in vivo. Treatment of either intact males, intact females, or ovariectomized (ovx) mice with 80 microg/kg/day of human parathyroid hormone (hPTH), for 5 to 11 days increased luciferase levels in tibiae by two- to threefold compared with vehicle-treated mice. The increases were tissue specific, as no changes in skin luciferase expression were observed. Treatment with prostaglandin E2, a potent bone anabolic agent, for 11 days also increased expression of the transgene in bone, but not in skin. Treatment with dihydrotestosterone (DHT) for 11 days increased luciferase activity in skin, but not in bone. Histomorphometric analysis revealed that 28-day treatment with PTH increased bone formation; 60-day treatment of OVX mice with DHT did not. These findings show a correlation between bone formation and the expression of a transgene driven by DNA elements of the mouse pro-alpha1 (I) collagen promoter, suggesting that this expression can be used as an indicator and provide a faster readout for the ability of agents to stimulate bone formation in this mouse strain.
authors.affiliation: Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Opas
authors.forename: M A
authors.initials: MA
authors.lastname: Gentile
authors.forename: J A
authors.initials: JA
authors.lastname: Rossert
authors.forename: B
authors.initials: B
authors.lastname: de Crombrugghe
authors.forename: G A
authors.initials: GA
authors.lastname: Rodan
authors.forename: A
authors.initials: A
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology; D013196:Dihydrotestosterone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011347:Procollagen / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D019076:Transgenes
chemical_list: D010281:Parathyroid Hormone; D011347:Procollagen; D013196:Dihydrotestosterone; D008156:Luciferases; D015232:Dinoprostone