Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice.
The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bone-sparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα(flox/flox) mice to generate mice lacking ERα protein expression specifically in osteocytes (Dmp1-ERα(-/-)). Male Dmp1-ERα(-/-) mice displayed a substantial reduction in trabecular bone volume (-20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (-45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα(-/-) mice. The male Dmp1-ERα(-/-) mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ERα(-/-) female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα(-/-) female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα(-/-) mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.
Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy,  University of Gothenburg, 413 45 Gothenburg,  Sweden.
Sara H
SH
Windahl
Anna E
AE
Börjesson
Helen H
HH
Farman
Cecilia
C
Engdahl
Sofia
S
Movérare-Skrtic
Klara
K
Sjögren
Marie K
MK
Lagerquist
Jenny M
JM
Kindblom
Antti
A
Koskela
Juha
J
Tuukkanen
Paola
P
Divieti Pajevic
Jian Q
JQ
Feng
Karin
K
Dahlman-Wright
Per
P
Antonson
Jan-Åke
JÅ
Gustafsson
Claes
C
Ohlsson
D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D010011:Osteocytes / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology; D012727:Sex Characteristics; D013314:Stress, Mechanical
D047628:Estrogen Receptor alpha; D004958:Estradiol