Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis.
The role of estrogens in the regulation of pubertal growth independently of GH and its receptor was studied in male mice with disrupted GHRKO. E(2) rescued skeletal growth rates in GHRKO associated with an increase in hepatic and serum IGF-I. These data show that E(2) rescues pubertal growth during GH resistance through a novel mechanism of GHR-independent stimulation of hepatic IGF-I production.


BACKGROUND
Growth hormone (GH) and estrogen play a pivotal role in pubertal growth and bone mineral acquisition. Estrogens can affect GH secretion and thereby provide a GH-dependent mechanism for their effects on skeletal growth. It is presently unclear if or to what extent estrogens are able to regulate pubertal growth and bone mineral accrual independently of GH and its receptor.


METHODS
Estradiol (E(2); 0.03 mug/day by subcutaneous silastic implants) was administered to orchidectomized (ORX) male mice with disrupted GHR (GHRKO) and corresponding WTs during late puberty (6-10 weeks). Longitudinal and radial bone growth, IGF-I in serum and its expression in liver, muscle, and bone, and liver gene expression were studied by histomorphometry, RIA, RT-PCR, microarrays, and Western blotting, respectively.


RESULTS
E(2) stimulated not only longitudinal (femur length and growth plate thickness) and radial growth (cortical thickness and periosteal perimeter), but also rescued longitudinal and periosteal growth rates in ORX GHRKO, whereas no significant changes occurred in WT. E(2) thereby upregulated serum IGF-I and liver IGF-I synthesis (+21% and +52%, respectively) in ORX GHRKO, whereas IGF-I synthesis in femur or muscle was unaffected. Study of the underlying mechanism of the stimulation of hepatic IGF-I expression showed that E(2) restored downregulated receptor signaling systems, such as the estrogen receptor alpha and the prolactin receptor. E(2) thereby recovered the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway as evidenced by a significantly increased activation of the transcription factor STAT5 in ORX GHRKO.


CONCLUSIONS
Our data show a stimulation of skeletal growth through upregulation of hepatic IGF-I by a hormone other than GH. E(2) rescues pubertal skeletal growth during GH resistance through a novel mechanism of GHR-independent stimulation of IGF-I synthesis in the liver.
Venken
Katrien
K
Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Belgium.
Schuit
Frans
F
Van Lommel
Leentje
L
Tsukamoto
Katsura
K
Kopchick
John J
JJ
Coschigano
Karen
K
Ohlsson
Claes
C
Movérare
Sofia
S
Boonen
Steven
S
Bouillon
Roger
R
Vanderschueren
Dirk
D
D000818:Animals; D001846:Bone Development / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D005269:Femur / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics; D006132:Growth Plate / Q000033:anatomy & histology / Q000254:growth & development; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013977:Tibia / Q000033:anatomy & histology / Q000254:growth & development
D002352:Carrier Proteins; D006023:Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C075944:insulin-like growth factor binding protein, acid labile subunit; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D011388:Prolactin