title: Suppressive function of androgen receptor in bone resorption.
abstract: As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-kappaB ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from AR-deficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.
authors.affiliation: Institute of Molecular and Cellular Biosciences and Department of Orthopedic Surgery, Faculty of Medicine, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kawano
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D013734:Androgen-Insensitivity Syndrome / Q000235:genetics; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics; D001862:Bone Resorption; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011944:Receptors, Androgen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011944:Receptors, Androgen; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse