The gene for aromatase, a rate-limiting enzyme for local estrogen biosynthesis, is a downstream target gene of Runx2 in skeletal tissues.
The essential osteoblast-related transcription factor Runx2 and the female steroid hormone estrogen are known to play pivotal roles in bone homeostasis; however, the functional interaction between Runx2- and estrogen-mediated signaling in skeletal tissues is minimally understood. Here we provide evidence that aromatase (CYP19), a rate-limiting enzyme responsible for estrogen biosynthesis in mammals, is transcriptionally regulated by Runx2. Consistent with the presence of multiple Runx2 binding sites, the binding of Runx2 to the aromatase promoter was demonstrated in vitro and confirmed in vivo by chromatin immunoprecipitation assays. The bone-specific aromatase promoter is activated by Runx2, and endogenous aromatase gene expression is upregulated by Runx2 overexpression, establishing the aromatase gene as a target of Runx2. The biological significance of the Runx2 transcriptional control of the aromatase gene is reflected by the enhanced estrogen biosynthesis in response to Runx2 in cultured cells. Reduced in vivo expression of skeletal aromatase gene and low bone mineral density are evident in Runx2 mutant mice. Collectively, these findings uncover a novel link between Runx2-mediated osteoblastogenic processes and the osteoblast-mediated biosynthesis of estrogen as an osteoprotective steroid hormone.
Jeong
Jae-Hwan
JH
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 101 Dongin-Dong, Jung-Gu, Daegu 700-422, Republic of Korea.
Jung
Youn-Kwan
YK
Kim
Hyo-Jin
HJ
Jin
Jung-Sook
JS
Kim
Hyun-Nam
HN
Kang
Sang-Min
SM
Kim
Shin-Yoon
SY
van Wijnen
Andre J
AJ
Stein
Janet L
JL
Lian
Jane B
JB
Stein
Gary S
GS
Kato
Shigeaki
S
Choi
Je-Yong
JY
D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D015519:Bone Density; D001842:Bone and Bones / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology; D004967:Estrogens / Q000096:biosynthesis*; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000201:enzymology / Q000502:physiology; D011374:Progesterone / Q000378:metabolism; D011401:Promoter Regions, Genetic
D050659:Core Binding Factor Alpha 1 Subunit; D004967:Estrogens; C493716:Runx2 protein, mouse; D011374:Progesterone; D001141:Aromatase