Estrogen Receptor α Mediates Proliferation of Osteoblastic Cells Stimulated by Estrogen and Mechanical Strain, but Their Acute Down-regulation of the Wnt Antagonist Sost Is Mediated by Estrogen Receptor β

Galea, Gabriel L.; Meakin, Lee B; Sugiyama, Toshihiro; Zebda, Noureddine; Sunters, Andrew; Taipaleenmäki, Hanna; Stein, Gary S.; Wijnen, André J. van; Lanyon, Lance E.; Price, Joanna S.

doi:10.1074/jbc.m112.405456

Cited by 112 publications

(135 citation statements)

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“…Osteoporosis is associated with osteoclast proliferation [61], and thus, bone loss was prevented by stimulating the process of osteoblast proliferation and suppressing the process of osteoclastogenesis in the OVX mice [62]. Osteoblast proliferation is regulated via binding to the ERE of the E 2 -ER complex and ERK activation [63,64]. In addition, Proliferation of osteoblasts shows ALP activity, which is greatly enhanced during in vitro bone formation [65].…”

Section: Discussionmentioning

confidence: 97%

Glutamic acid ameliorates estrogen deficiency–induced menopausal-like symptoms in ovariectomized mice

et al. 2015

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Section: Discussionmentioning

confidence: 97%

Glutamic acid ameliorates estrogen deficiency–induced menopausal-like symptoms in ovariectomized mice

et al. 2015

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“…These findings were supported by in vitro studies in which primary long bone osteoblasts isolated from ERKO mice exhibited no strain-related increase in proliferation, whereas osteoblasts isolated from BERKO mice exhibited a 125% increase in cell number following mechanical strain (29). Finally, Galea et al (18) has provided evidence that both strain and estrogen work through ER␤ to downregulate Sost expression, which in turn enhances osteogenic activity (49a). Taken together, these data suggest that both ER␣ and ER␤ can regulate mechanical signaling in bone and influence bone adaptation and that the ER␤ itself or signaling via ER␤ may normally oppose mechanical signaling via ER␣ in osteoblasts.…”

mentioning

confidence: 86%

“…In addition, ER␣ appears to also be required for Wnt/␤-catenin signaling (2). Galea et al (18) showed that flow activated nuclear accumulation of ␤-catenin and activated the TCF/LEF promoter in ROS 17/2.8 cells. This response was inhibited by treatment with the ER modulator ICI-182,780 and the GSK-3␤ inhibitor lithium chloride.…”

Section: E941 Er␤ Regulates Mechanical Signalingmentioning

confidence: 99%

“…In addition, this response was not observed in ER␣ Ϫ/Ϫ mice, suggesting that ER␣ is required for Wnt/␤-catenin signaling in response to mechanical loading. More recently, the same group showed that both strain and estrogen work through ER␤ to downregulate Sost expression (18), a gene that inhibits Wnt signaling and attenuates osteoblast bone formation. Thus, Wnt signaling can be regulated by both ER␣ and ER␤.…”

Section: E941 Er␤ Regulates Mechanical Signalingmentioning

confidence: 99%

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Estrogen receptor-β regulates mechanical signaling in primary osteoblasts

Castillo

Triplett

Pavalko

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Castillo AB, Triplett JW, Pavalko FM, Turner CH. Estrogen receptor-␤ regulates mechanical signaling in primary osteoblasts. Am J Physiol Endocrinol Metab 306: E937-E944, 2014. First published March 11, 2014; doi:10.1152/ajpendo.00458.2013.-Mechanical loading is an important regulator in skeletal growth, maintenance, and aging. Estrogen receptors have a regulatory role in mechanically induced bone adaptation. Estrogen receptor-␣ (ER␣) is known to enhance load-induced bone formation, whereas ER␤ negatively regulates this process. We hypothesized that ER␤ regulates mechanical signaling in osteoblasts. We tested this hypothesis by subjecting primary calvarial cells isolated from wild-type and ER␤-knockout mice (BERKO) to oscillatory fluid flow in the absence or presence of estradiol (E 2). We found that the known responses to fluid shear stress, i.e., phosphorylation of the mitogen-activated protein kinase ERK and upregulation of COX-2 expression, were inhibited in BERKO cells in the absence of E2. Flow-induced increase in prostaglandin E2 (PGE2) release was not altered in BERKO cells in the absence of E2, but was increased when E2 was present. Additionally, immunofluorescence analysis and estrogen response element luciferase assays revealed increased ER␣ expression and flow-and ligand-induced nuclear translocation as well as transcriptional activity in BERKO cells in both the presence and absence of E 2. Taken together, these data suggest that ER␤ plays both ligand-dependent and ligand-independent roles in mechanical signaling in osteoblasts. Furthermore, our data suggest that one mechanism by which ER␤ regulates mechanotransduction in osteoblasts may result from its inhibitory effect on ER␣ expression and function. Targeting estrogen receptors (e.g., inhibiting ER␤) may represent an effective approach for prevention and treatment of age-related bone loss. estrogen receptor-␤; osteoblast; mechanobiology; cyclooxygenase-2; prostaglandin E 2 MECHANICAL LOADING IS AN IMPORTANT REGULATOR in skeletal growth, maintenance, and aging (25,41,47). Increased bone formation is observed typically with increased mechanical loading, whereas bone loss is observed with decreased mechanical loading or disuse (27,48). Current evidence suggests that mechanical stress is sensed by osteocytes, which then signal osteoblasts and osteoclasts to either add or remove bone, respectively (5). The mechanism by which a physical stimulus is transformed into a biochemical signal, termed mechanotransduction, remains unclear (6).Estrogen is a key regulator of bone formation. During growth, radial expansion of long bones occurs at similar rates in boys and girls. However, at the onset of puberty, when estrogen levels increase in girls, periosteal expansion is inhibited (44). Conversely, at the onset of menopause, when estrogen levels fall in women, radial expansion recommences, suggesting that estrogen inhibits periosteal bone apposition (19). Estrogen also appears to inhibit exercise-induced periosteal expansion (4, 25).The mechanism for opposing ef...

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“…LRP5-deficient mice were used and showed that the LRP5 mutation was associated with increased response to loading [76], while sclerostindeficient mice demonstrated that long-term sclerostin deficiency can result in increased bone formation [77]. Many studies using germ-line and targeted protein knockouts for estrogen and androgen pathways have investigated the role these pathways play in governing the response to mechanical loading [78][79][80][81]. A detailed discussion of these studies is beyond the scope of this paper but the reader is directed to a recent review on the topic [82].…”

Section: Page 8 Of 22mentioning

confidence: 99%

Bone Quality and Quantity are Mediated by Mechanical Stimuli

Berman

Wallace

2016

Clinic Rev Bone Miner Metab

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Prevention of fracture through improved bone mechanical strength is of great importance given the large number of bone disease-related fractures each year, the decreased quality of life associated with fractures, and the large anticipated increase in fracture incidence over the upcoming years due to the aging population. Exercise and other forms of mechanical stimulation have been shown to increase bone mass, suggesting improved strength. However, while bone mass is a good indicator of strength, other components (such as bone quality) also contribute to bone mechanical integrity. While increased bone mass has been explored considerably using both exercise and targeted loading models, the role of mechanical stimulation in altering bone quality has been explored to a lesser degree. Understanding how to improve both the quantity and quality of bone is critical to increasing fracture resistance. Herein, we discuss quantity and quality-based improvements that have been observed using both exercise and targeted loading models of bone adaptation.

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Estrogen Receptor α Mediates Proliferation of Osteoblastic Cells Stimulated by Estrogen and Mechanical Strain, but Their Acute Down-regulation of the Wnt Antagonist Sost Is Mediated by Estrogen Receptor β

Cited by 112 publications

References 123 publications

Glutamic acid ameliorates estrogen deficiency–induced menopausal-like symptoms in ovariectomized mice

Glutamic acid ameliorates estrogen deficiency–induced menopausal-like symptoms in ovariectomized mice

Estrogen receptor-β regulates mechanical signaling in primary osteoblasts

Bone Quality and Quantity are Mediated by Mechanical Stimuli

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