TY - JOUR
T1 - Estrogen receptor alpha signaling in extrahypothalamic neurons during late puberty decreases bone size and strength in female but not in male mice
AU - Kim, Na Ri
AU - Jardí, Ferran
AU - Khalil, Rougin
AU - Antonio, Leen
AU - Schollaert, Dieter
AU - Deboel, Ludo
AU - van Lenthe, G. Harry
AU - Decallonne, Brigitte
AU - Carmeliet, Geert
AU - Gustafsson, Jan Åke
AU - Claessens, Frank
AU - Ohlsson, Claes
AU - Lagerquist, Marie K.
AU - Dubois, Vanessa
AU - Vanderschueren, Dirk
N1 - Publisher Copyright:
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Sexually dimorphic bone structure emerges largely during puberty. Sex steroids are critical for peak bone mass acquisition in both genders. In particular, the biphasic effects of estrogens mediate the skeletal sexual dimorphism. However, so far the stimulatory vs inhibitory actions of estrogens on bone mass are not fully explained by direct effects on bone cells. Recently, it has become evident that there is possible neuroendocrine action of estrogen receptor alpha (ERα) on the skeleton. Based on these considerations, we hypothesized that neuronal ERα-signaling may contribute to the skeletal growth during puberty. Here, we generated mice with tamoxifen-inducible Thy1-Cre mediated ERα inactivation during late puberty specifically in extrahypothalamic neurons (N-ERαKO). Inactivation of neuronal ERα did not alter the body weight in males, whereas N-ERαKO females exhibited a higher body weight and increased body and bone length compared to their control littermates at 16 weeks of age. Ex vivo microCT analysis showed increased radial bone expansion of the midshaft femur in female N-ERαKO along with higher serum levels of insulin-like growth factor (IGF)-1 as well as IGF-binding protein (IGFBP)-3. Furthermore, the 3-point bending test revealed increased bone strength in female N-ERαKO. In contrast, inactivation of neuronal ERα had no major effect on bone growth in males. In conclusion, we demonstrate that central ERα-signaling limits longitudinal bone growth and radial bone expansion specifically in females potentially by interacting with the GH/IGF-1 axis.
AB - Sexually dimorphic bone structure emerges largely during puberty. Sex steroids are critical for peak bone mass acquisition in both genders. In particular, the biphasic effects of estrogens mediate the skeletal sexual dimorphism. However, so far the stimulatory vs inhibitory actions of estrogens on bone mass are not fully explained by direct effects on bone cells. Recently, it has become evident that there is possible neuroendocrine action of estrogen receptor alpha (ERα) on the skeleton. Based on these considerations, we hypothesized that neuronal ERα-signaling may contribute to the skeletal growth during puberty. Here, we generated mice with tamoxifen-inducible Thy1-Cre mediated ERα inactivation during late puberty specifically in extrahypothalamic neurons (N-ERαKO). Inactivation of neuronal ERα did not alter the body weight in males, whereas N-ERαKO females exhibited a higher body weight and increased body and bone length compared to their control littermates at 16 weeks of age. Ex vivo microCT analysis showed increased radial bone expansion of the midshaft femur in female N-ERαKO along with higher serum levels of insulin-like growth factor (IGF)-1 as well as IGF-binding protein (IGFBP)-3. Furthermore, the 3-point bending test revealed increased bone strength in female N-ERαKO. In contrast, inactivation of neuronal ERα had no major effect on bone growth in males. In conclusion, we demonstrate that central ERα-signaling limits longitudinal bone growth and radial bone expansion specifically in females potentially by interacting with the GH/IGF-1 axis.
KW - GH/IGF-1
KW - neuroendocrine bone axis
KW - puberty
KW - sex steroids
KW - skeletal sexual dimorphism
KW - Signal Transduction
KW - Mice, Inbred C57BL
KW - Sexual Maturation/genetics
KW - Male
KW - Sex Characteristics
KW - X-Ray Microtomography
KW - Bone Development/genetics
KW - RNA, Messenger/genetics
KW - Mice, Knockout
KW - Bone and Bones/anatomy & histology
KW - Biomechanical Phenomena
KW - Animals
KW - Neurons/metabolism
KW - Female
KW - Mice
KW - Bone Density/genetics
KW - Estrogen Receptor alpha/deficiency
UR - http://www.scopus.com/inward/record.url?scp=85082831463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082831463&partnerID=8YFLogxK
U2 - 10.1096/fj.202000272R
DO - 10.1096/fj.202000272R
M3 - Article
C2 - 32239553
AN - SCOPUS:85082831463
SN - 0892-6638
VL - 34
SP - 7118
EP - 7126
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -