Mechanical Strain and Estrogen Activate Estrogen Receptor α in Bone Cells

Jessop, Helen; Sjöberg, Maria; Cheng, Ming Zhao; Zaman, Gul; Wheeler‐Jones, Caroline P.D.; Lanyon, Lance E.

doi:10.1359/jbmr.2001.16.6.1045

Cited by 110 publications

(80 citation statements)

References 49 publications

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“…Studies in osteoblastic and other cells demonstrated acute (minutes to hours) and/or delayed (days) ERK1/2 activation in response to different extracellular stimuli. Rapid responses that are sustained for several days were also reported (5,35,36). The acute response is attributable to direct, primary receptor-triggered phosphorylation events, whereas the delayed ERK1/2 activation is thought to be preceded by events such as calcium mobilization, prostaglandin production, and protein synthesis (37,38).…”

Section: Discussionmentioning

confidence: 96%

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel

Namdar-Attar

Noh

et al. 2005

Journal of Biological Chemistry

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In osteoblasts, the mitogen-activated protein kinases ERK1/2 and p38 as well as the cAMP-response element-binding protein (CREB) have been implicated in the regulation of proliferation and differentiation. The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing. OGP-(10 -14) is the physiologically active form of OGP. Using gene array analysis, real-time reverse transcription-PCR, and immunoblot and DNA synthesis assays we show here that in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures the OGP-(10 -14) mitogenic signaling is critically dependent on de novo synthesis of mitogen-activated protein kinase-activated protein kinase 2 (Mapkapk2) mRNA and protein.The increase in Mapkapk2 occurs following short term (5-60 min) stimulation of ERK1/2 activity by OGP-(10 -14); phosphorylation of p38 remains unaffected. Downstream of Mapkapk2, CREB is phosphorylated on Ser 133 leading to its enhanced transcriptional activity. That these events are critical for the OGP-(10 -14) mitogenic signaling is demonstrated by blocking the effects of OGP-(10 -14) on the ERK1/2 pathway, Mapkapk2, CREB, and DNA synthesis using the MEK inhibitor PD098059. The OGP-(10 -14) stimulation of CREB transcriptional activity and DNA synthesis is also blocked by Mapkapk2 siRNA. These data define a novel mitogenic signaling pathway in osteoblasts whereby ERK1/2 stimulation of CREB phosphorylation and transcriptional activity as well as DNA synthesis are critically dependent on de novo Mapkapk2 synthesis.In mammalian cells, the family of mitogen-activated protein (MAP) 3 kinases provides a key link between membrane-bound receptors and changes in the pattern of gene expression. The MAP kinases are activated downstream of many different types of receptors, including tyrosine kinase receptors, cytokine receptors, and serpentine G-protein coupled receptors (1, 2). The MAP kinases consist of four subfamilies: the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase/stress-activated kinase, p38 MAP kinase, and ERK 5. Further downstream, they regulate a multitude of transcription factors that control cell proliferation, survival, and differentiation (3, 4). In osteoblasts, ERK1/2-dependent phosphorylation cascades have been implicated in the regulation of proliferation and RUNX2 activity (5, 6). Activation of p38 has been demonstrated in osteoblasts undergoing differentiation after stimulation with bone morphogenetic protein-2 and epidermal growth factor (7,8).The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing when administered to mice and rats (9 -11). Transgenic mice overexpressing OGP have a markedly increased peak bone mass (12). OGP is present in mammalian serum in micromolar concentrations mainly complexed to ␣ 2 -macroglobulin (13). Upon its dissociation from the complex, it is proteolytically activated yieldin...

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Section: Discussionmentioning

confidence: 96%

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel

Namdar-Attar

Noh

et al. 2005

Journal of Biological Chemistry

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“…Bikle and co-workers (26,27) have also demonstrated that skeletal unloading induces resistance to IGF-I to induce bone formation, which is caused by inhibition of the IGF-I signaling pathway through down-regulation of the integrin pathway. Regarding the ER signaling pathway, Lanyon and co-workers (25,(43)(44)(45)(46) have provided compelling evidence that ER, especially ER␣, is essential for mechanical stimulation of bone formation. Specifically, they showed that knocking out the ER␣ (Esr1) expression in mice completely abolished the osteogenic response to mechanical loading in vivo (45) and in vitro (46).…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Lau

Kapur

Kesavan

et al. 2006

Journal of Biological Chemistry

149

138

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C57BL/6J (B6), but not C3H/HeJ (C3H), mice responded to mechanical loading with an increase in bone formation. A 30-min steady fluid shear of 20 dynes/cm 2 increased [ 3 H]thymidine incorporation and alkaline phosphatase activity and up-regulated the expression of early mechanoresponsive genes (integrin ␤1 (Igtb1) and cyclooxygenase-2 (Cox-2)) in B6 but not C3H osteoblasts, indicating that the differential mechanosensitivity was intrinsic to osteoblasts. In-house microarray analysis with 5,500 gene fragments revealed that the expression of 669 genes in B6 osteoblasts and 474 genes in C3H osteoblasts was altered 4 h after the fluid shear. Several genes associated with the insulin-like growth factor (IGF)-I, the estrogen receptor (ER), the bone morphogenetic protein (BMP)/transforming growth factor-␤, and Wnt pathways were differentially up-regulated in B6 osteoblasts. In vitro mechanical loading also led to up-regulation of these genes in the bones of B6 but not C3H mice. Pretreatment of B6 osteoblasts with inhibitors of the Wnt pathway (endostatin), the BMP pathway (Noggin), or the ER pathway (ICI182780) blocked the fluid shear-induced proliferation. Inhibition of integrin and Cox-2 activation by echistatin and indomethacin, respectively, each blocked the fluid shear-induced up-regulation of genes associated with these four pathways. In summary, up-regulation of the IGF-I, ER, BMP, and Wnt pathways is involved in mechanotransduction. These four pathways are downstream to the early mechanoresponsive genes, i.e. Igtb1 and Cox-2. In conclusion, differential up-regulation of these anabolic pathways may in part contribute to the good and poor response, respectively, in the B6 and C3H mice to mechanical loading.Mechanical loading is essential for maintenance of skeletal architectural integrity. Loading stimulates bone formation and suppresses bone resorption, leading to an overall increase in bone mass (1), whereas unloading results in an overall decrease in bone mass, because of an inhibition of formation along with an increase in resorption (2). Loading produces strains in the mineralized matrix of bone, which generates interstitial fluid flow through lacunar/canalicular spaces (3). This fluid flow exerts a shear stress at surfaces of osteoblasts and osteocytes lining these spaces, which generates biochemical signals to produce biological effects. Multiple interacting signaling pathways are involved in translating the fluid shear signals into biological effects in bone cells (4), and these pathways are collectively referred to as the mechanotransduction mechanism. Mechanical loading is a key regulatory process for bone mass and strength (5). Knowledge of the mechanotransduction mechanism would not only yield information about the mechanical stimulation of bone formation but would also provide insights into the pathophysiology of osteoporosis and other bone-wasting diseases.There is increasing evidence that genetics play a major part in determining the bone response to mechanical loading. Studies from our group (6, 7...

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“…(14)(15)(16)(17)(18) Several reports indicate that bone cells respond to mechanical strain and estrogen through the same signaling pathways. (19)(20)(21)(22) We have previously shown that both PA and a polymorphism in the estrogen degrading enzyme catechol-Omethyltransferase (COMT) are associated with areal BMD (aBMD) and trabecular volumetric BMD (vBMD) in young men. (23,24) The investigated COMT polymorphism constitutes a functional G to A polymorphism, which results in a valine to methionine substitution at codon 158.…”

Section: Introductionmentioning

confidence: 99%

Association Between Physical Activity and BMD in Young Men Is Modulated by Catechol-O-Methyltransferase (COMT) Genotype: The GOOD Study

Lorentzon

Eriksson

Nilsson

et al. 2007

Journal of Bone and Mineral Research

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ABSTRACT:In this large population-based study in young men, we show that the COMT val158met polymorphism modulates the association between physical activity, aBMD (DXA), and trabecular vBMD (pQCT).Introduction: Peak BMD is an important predictor of future risk of osteoporosis and is largely determined by genetic factors but also by environmental factors, among which physical activity (PA) is a strong contributor. Estrogens are believed to influence the mechanical strain signal generated by bones subjected to mechanical loading. Catechol-O-methyltransferase (COMT) is involved in the degradation of estrogens. A functional polymorphism in the COMT gene (val158met), results in a 60-75% difference in enzyme activity between the val (high activity ‫ס‬ H) and met (low activity ‫ס‬ L) variants. The aim of this study was to determine if the COMT val158met polymorphism modulates the association between PA and BMD in young men. Materials and Methods:The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men (age, 18.9 ± 0.6 yr). Areal BMD (aBMD) was measured by DXA, whereas cortical and trabecular volumetric BMD (vBMD) were measured by pQCT. Study subjects were genotyped and classified as COMT

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Mechanical Strain and Estrogen Activate Estrogen Receptor α in Bone Cells

Cited by 110 publications

References 49 publications

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Association Between Physical Activity and BMD in Young Men Is Modulated by Catechol-O-Methyltransferase (COMT) Genotype: The GOOD Study

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