Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice

Vidal, Olle; Lindberg, Mattias F.; Hollberg, Karin; Baylink, David J.; Andersson, Göran; Lubahn, Dennis B.; Mohan, Subburaman; Gustafsson, Jan‐Åke; Ohlsson, Claes

doi:10.1073/pnas.97.10.5474

Cited by 350 publications

(308 citation statements)

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“…In contrast, male mice with inactivation of ERa in all tissues had a reduced skeletal growth during sexual maturation associated with reduced serum IGF-1 levels and disturbed GH secretion, as indicated by reduced MUP expression in the liver. (17) These findings suggest that indirect, probably GH/IGF-1-mediated effects not requiring ERa in growth plate cartilage are responsible for the role of ERa in modulating skeletal growth during early sexual maturation. An indirect effect via the GH/IGF-1 axis during early sexual maturation is supported by findings from children with idiopathic precocious puberty of central origin (CPP).…”

Section: Discussionmentioning

confidence: 86%

“…(10)(11)(12)(13)(14)(15)(16) ERa is the main functional ER in the mouse growth plate, although ERb slightly modulates longitudinal bone growth in female but not in male mice. (17,18) We recently demonstrated that female GPR30 À/À mice displayed reduced longitudinal bone growth and reduced growth plate height that could not be reduced further by E2 treatment. (12,15) At the current stage of knowledge, it is difficult to evaluate whether GPR30 is a functional ER in the growth plate or whether the growth phenotype of female GPR30 À/À mice is secondary to other phenotypes.…”

Section: J Jbmrmentioning

confidence: 99%

“…(2,(20)(21)(22) An indirect stimulatory effect of estrogens via effects on the GH/IGF-1 axis is supported by the finding that during sexual maturation, male ERainactivated mice display reduced longitudinal bone growth associated with reduced serum IGF-1 levels. (17) Despite the well-known effects of estrogens on longitudinal bone growth, data from in vitro experiments are inconclusive. There are reports of estrogens stimulating, (1,(23)(24)(25) inhibiting, (26,27) or having no effect (28) on chondrocyte proliferation.…”

Section: J Jbmrmentioning

confidence: 99%

“…Cortical bone parameters (cortical vBMD and cortical thickness) were analyzed in the middiaphyseal region of the tibia. (17) Quantitative histology of growth plates Distal femur was fixed in 4% paraformaldehyde, decalcified in 10% EDTA, and embedded in paraffin. Sections (5 mm thick) were stained with alcian blue/van Gieson.…”

Section: Peripheral Quantitative Computed Tomography (Pqct)mentioning

confidence: 99%

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The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Börjesson

Lagerquist

Liu

et al. 2010

Journal of Bone and Mineral Research

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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 ERa in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERa. Although mice with total ERa 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 cartilagespecific ERa 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 ERa À/À mice. Adult cartilage-specific ERa À/À 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 ERa À/À mice compared with control mice. We conclude that during early sexual maturation, ERa 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. ß

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Section: Discussionmentioning

confidence: 86%

Section: J Jbmrmentioning

confidence: 99%

Section: J Jbmrmentioning

confidence: 99%

Section: Peripheral Quantitative Computed Tomography (Pqct)mentioning

confidence: 99%

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The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Börjesson

Lagerquist

Liu

et al. 2010

Journal of Bone and Mineral Research

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“…The ERα concentrations in rat OB cells increase by almost 10-fold during the differentiation of OB precursor cells into mature OBs, whereas ERβ concentrations increase only slightly, but remain high at all stages [Onoe et al, 1997]. ERβ is the primary ER found in cancellous bone while ERα is more highly expressed in cortical bone [Onoe et al, 1997;Bord et al, 2001b].Studies utilizing mice, deficient forERα, ERβ, or both, have yielded significant insight into the role of these receptors in the skeleton [Vidal et al, 2000;Sims et al, 2002Sims et al, , 2003. Interestingly, deletion of ERα in mice leads to a decrease in bone turnover and an increase in cancellous bone volume in both male and female animals.…”

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confidence: 99%

Estrogen‐TGFβ cross‐talk in bone and other cell types: Role of TIEG, Runx2, and other transcription factors

Hawse

Subramaniam

Ingle

et al. 2007

J of Cellular Biochemistry

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It is well established that E 2 and TGFβ have major biological effects in multiple tissues, including bone. The signaling pathways through which these two factors elicit their effects are well documented. However, the interaction between these two pathways and the potential consequences of cross-talk between E 2 and TGFβ continue to be elucidated. In this prospectus, we present known and potential roles of TIEG, Runx2, and other transcription factors as important mediators of signaling between these two pathways. KeywordsBone; Runx2; TIEG; Estrogen; TGFβ; osteoblast; osteoclast Estrogen (E 2 ) and TGFβ are known to be major regulators of skeletal formation and maintenance Spelsberg et al., 1999;Rickard et al., 2002a;Janssens et al., 2005]. In the past there have been numerous reports about the interaction (cross-talk) between these two important regulators, many of which involve transcription factors. This prospectus summarizes some of these studies and proposes some potential areas of crosstalk in osteoblast (OB) cells which includes Runx2 and another important factor discovered by our laboratory, the TGFβ inducible early gene-1 (TIEG), also known as Krüppel-like transcription factor-10 (KLF-10) [Subramaniam et al., 1995]. ESTROGEN ACTION IN OB CELLSThe skeleton is one of the main targets of E 2 action in the body as it regulates bone growth and remodeling. Estrogen has major effects on OB and osteoclast (OC) differentiation, including OB proliferation, differentiation, matrix production, and mineralization [Hughes et al., 1996;Robinson and Spelsberg, 1997;Oursler, 1998;Khosla et al., 1999;Rickard et al., 1999Rickard et al., , 2002aSpelsberg et al., 1999]. Decreased E 2 levels are known to be one of the main causes of osteoporosis [Melton, 1995;Gallagher, 1996] and there is abundant evidence demonstrating a critical role for E 2 in regulating bone metabolism and homeostasis in both [Riggs et al., 2002]. It is important to understand E 2 action in the skeleton to better define the mechanisms of bone loss and in order to develop new approaches to prevent and treat osteoporosis. The primary mechanism by which E 2 elicits its effects on target tissues is by binding to, and activating, the two major estrogen receptor (ER) isoforms, ERα and ERβ. It was originally believed that ERβ only modulated the activity of ERα; however, recent studies by our laboratory and others have demonstrated that these two receptors regulate distinct sets of genes in OBs [Waters et al., 2001;Rickard et al., 2002b;Monroe et al., 2003a;Kian Tee et al., 2004;Stossi et al., 2004;Monroe et al., 2005]. Adding to this complexity is the identification of a host of nuclear receptor co-activators and corepressors that modulate E 2 action [McKenna et al., 1999]. OBs express both ERα and ERβ, and both are differentially expressed during OB maturation. The ERα concentrations in rat OB cells increase by almost 10-fold during the differentiation of OB precursor cells into mature OBs, whereas ERβ concentrations increase only slightly, but remain ...

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Fetal Calcium Metabolism

Kovacs¹

2013

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice

Cited by 350 publications

References 59 publications

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Estrogen‐TGFβ cross‐talk in bone and other cell types: Role of TIEG, Runx2, and other transcription factors

Fetal Calcium Metabolism

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