Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts.
Estrogen plays important roles in maintaining bone density and protecting against osteoporosis, but the underlying mechanisms of estrogen action via estrogen receptors (ERs) in bone remain to be clarified. In the present study, we isolated primary osteoblasts derived from transgenic rats harboring a dominant negative ER mutant, rat ERalpha (1-535) cDNA, and from their wild-type littermates. We observed that the rate of cell growth of osteoblasts from the transgenic rats was reduced compared to that of wild-type osteoblasts. Utilizing cDNA microarray analysis, we found that mRNA level of cyclin D2 was lower in the osteoblasts from the transgenic rats. D-type cyclins including cyclin D1, cyclin D2, and cyclin D3 are cell cycle regulators that promote progression through the early-to-mid G1 phase of the cell cycle. The protein levels of D-type cyclins including cyclin D2 and cyclin D3 but not cyclin D1 were elevated in wild-type osteoblasts with 17beta-estradiol treatment, resulting in the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6) activities and the promotion of cell growth. Moreover, an anti-estrogen ICI 182,780 abolished the induction of the expression of D-type cyclins by 17beta-estradiol. Our findings indicate that estrogen and its receptors enhance Cdk4/6 activities through the induction of D-type cyclins, leading to the growth promotion of osteoblasts.
Fujita
Masayo
M
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan.
Urano
Tomohiko
T
Horie
Kuniko
K
Ikeda
Kazuhiro
K
Tsukui
Tohru
T
Fukuoka
Hideoki
H
Tsutsumi
Osamu
O
Ouchi
Yasuyoshi
Y
Inoue
Satoshi
S
D000818:Animals; D030801:Animals, Genetically Modified; D002455:Cell Division; D002478:Cells, Cultured; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics; D015854:Up-Regulation
D056741:Cyclin D; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; C495903:Cdk4 protein, rat; C495913:Cdk6 protein, rat; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases