The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth.
Estrogens enhance skeletal growth during early sexual maturation, whereas high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. To determine the role of ERα in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERα. Although mice with total ERα inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-1 axis, the skeletal growth was normal during sexual maturation in mice with cartilage-specific ERα inactivation. High-dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERα(-/-) mice. Adult cartilage-specific ERα(-/-) mice continued to grow after 4 months of age, whereas growth was limited in control mice, resulting in increased femur length in 1-year-old cartilage-specific ERα(-/-) mice compared with control mice. We conclude that during early sexual maturation, ERα in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high-dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice.
Börjesson
Anna E
AE
Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden.
Lagerquist
Marie K
MK
Liu
Chen
C
Shao
Ruijin
R
Windahl
Sara H
SH
Karlsson
Camilla
C
Sjögren
Klara
K
Movérare-Skrtic
Sofia
S
Antal
Maria Christina
MC
Krust
Andrée
A
Mohan
Subburaman
S
Chambon
Pierre
P
Sävendahl
Lars
L
Ohlsson
Claes
C
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D010052:Ovariectomy; D012741:Sexual Maturation / Q000187:drug effects
D047628:Estrogen Receptor alpha; D004958:Estradiol