title: Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and estrogen but not raloxifene.
abstract: The pharmacological preservation of bone in the ovariectomized rat by estrogen, selective estrogen receptor modulators (SERMs), and bisphosphonates has been well described. However, comprehensive molecular analysis of the effects of these pharmacologically diverse antiresorptive agents on gene expression in bone has not been performed. This study used DNA microarrays to analyze RNA from the proximal femur metaphysis of sham and ovariectomized vehicle-treated rats, and ovariectomized rats treated for 35 days with maximally efficacious doses of 17-alpha ethinyl estradiol, the benzothiophene SERM, raloxifene, the benzopyran SERM, (S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-7-ol (EM652), and the aminobisphosphonate, alendronate. Ovariectomy resulted in 644 significant probe set changes relative to sham control rats (p < 0.05), whereas E2, raloxifene, EM652, and alendronate regulated 613, 765, 652, and 737 probe sets, respectively, relative to ovariectomized control rats. An intersection of these data sets yielded 334 unique genes that were altered after ovariectomy and additionally changed by one or more antiresorptive treatment. Clustering analysis showed that the transcript profile was distinctly different for each pharmaceutical agent and that raloxifene maintained more genes at sham levels than any other treatment. In addition, E2 and alendronate suppressed a cluster of genes associated with bone formation activity below that of sham, whereas raloxifene had little effect on these genes. These data indicate stronger suppressive effects of E2 and alendronate on bone formation activity and that ovariectomy plus raloxifene resembles sham more closely than ovariectomized animals treated with E2, EM652, or alendronate.
authors.affiliation: Endocrine Research Division, Lilly Research Labs, Indianapolis, IN 46285, USA. l.helvering@lilly.com
authors.forename: Leah M
authors.initials: LM
authors.lastname: Helvering
authors.forename: Riting
authors.initials: R
authors.lastname: Liu
authors.forename: Nalini H
authors.initials: NH
authors.lastname: Kulkarni
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.forename: Peining
authors.initials: P
authors.lastname: Chen
authors.forename: Shuguang
authors.initials: S
authors.lastname: Huang
authors.forename: Frank
authors.initials: F
authors.lastname: Lawrence
authors.forename: David L
authors.initials: DL
authors.lastname: Halladay
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Miles
authors.forename: Emily M
authors.initials: EM
authors.lastname: Ambrose
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Yanfei L
authors.initials: YL
authors.lastname: Ma
authors.forename: Charles A
authors.initials: CA
authors.lastname: Frolik
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Dow
authors.forename: Henry U
authors.initials: HU
authors.lastname: Bryant
authors.forename: Jude E
authors.initials: JE
authors.lastname: Onyia
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D019295:Computational Biology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004967:Estrogens; D010281:Parathyroid Hormone; D020849:Raloxifene Hydrochloride; D019386:Alendronate