title: Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts.
abstract: Estrogens play a key role in regulation of bone mass and strength by controlling activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Cellular effects of estrogens are mediated predominantly by the action of estrogen receptor alpha (ERalpha). In earlier studies, ablation of the ERalpha gene in mice did not result in osteoporotic phenotypes due to systemic endocrine disturbance and compensatory effects of elevated levels of testosterone. Despite the relatively well-established effects in osteoblasts, little is known about the direct action of estrogen in osteoclasts. Development in the last decade of more sophisticated genetic manipulation approaches opened new possibilities to explore cell-specific roles of nuclear receptors in bone tissue. Recently, we have generated osteoclast-specific ERalpha gene knockout mice and shown that in vivo estrogens directly regulate the life span of mature osteoclasts by inducing the expression of pro-apoptotic Fas ligand (FasL). Inhibitory effects of estrogens on osteoclast function were further studied in vitro. We observed sufficiently detectable ERalpha expression in osteoclasts differentiating from primary bone marrow cells or RAW264 cells, although levels of ERalpha were decreasing during progression of the differentiation into mature osteoclasts. Treatment with estrogens led to reduction in expression of osteoclast-specific genes controlling bone resorption activity. However, estrogens did not affect the size of multinucleated osteoclasts or number of nuclei in a mature osteoclast. In conclusion, in osteoclasts, estrogens function to inhibit bone resorption activity and vitality rather than differentiation.
authors.affiliation: Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Ming-Young
authors.initials: MY
authors.lastname: Youn
authors.forename: Shino
authors.initials: S
authors.lastname: Kondoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Alexander
authors.initials: A
authors.lastname: Kouzmenko
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000368:Aged; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000502:physiology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000517:prevention & control; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000502:physiology; D006410:Hematopoiesis; D006801:Humans; D008019:Life Style; D008124:Locomotion; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000502:physiology*; D010052:Ovariectomy; D017698:Postmenopause
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D012739:Gonadal Steroid Hormones