Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene

Cheung, J; Mak, Y. T.; Papaioannou, Stelios; Evans, Bronwen Alice James; Fogelman, Ignac; Hampson, Geeta

doi:10.1677/joe.0.1770423

Cited by 74 publications

(56 citation statements)

References 40 publications

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“…We demonstrate here that raloxifene can activate the classical signalling pathway in vivo in uterus. These data are contradictory to previous in vitro studies where uterine cancer cell lines show lack of raloxifene signalling via the classical pathway (Paech et al 1997, Cheung et al 2003, and OE 2 -induced proliferation of uterine epithelial cells is shown to be independent of the classical pathway (O'Brien et al 2006). Our analysis of IgfI expression, which is mediated via Ap1, supports the involvement of non-classical signalling in the regulation of the uterus by both OE 2 and raloxifene.…”

Section: Discussioncontrasting

confidence: 99%

“…Several studies have reported lack of raloxifene signalling via ERE in uterine cancer cell lines. Instead, the non-classical pathway, involving Ap1, is suggested to be more important in these cells (Paech et al 1997, Cheung et al 2003. In cultured osteoblasts, it has also been demonstrated that raloxifene may not initiate transcription via the classical pathway (Yang et al 1996b).…”

Section: Introductionmentioning

confidence: 99%

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In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Engdahl

Jochéms

Gustafsson

et al. 2009

Journal of Endocrinology

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Raloxifene is a selective oestrogen receptor modulator with tissue-specific effects. The mechanisms behind the effects of raloxifene are partly unclear, and the aim of the present study was to investigate whether raloxifene can activate the classical oestrogen-signalling pathway in vivo in three known oestrogen-responsive organs, uterus (reproductive organ), bone (non-reproductive organ) and thymus (immune organ). For this purpose, we have used reporter mice with a luciferase gene under control of oestrogen-responsive elements (EREs), enabling detection of in vivo activation of gene transcription via the classical oestrogen pathway. Three-month-old ovariectomized ERE-luciferase mice were treated with the raloxifene analogue (LY117018), oestradiol (OE 2 ) or vehicle for 3 weeks. Luciferase activation was measured in bone, uterus and thymus, and compared to bone parameters, and uterus and thymus weights. The raloxifene analogue affected bone mineral density (BMD) to the same extent as OE 2 , and both treatments resulted in increased luciferase activity in bone. As expected, OE 2 treatment resulted in increased uterus weight and increased uterine luciferase activity, while the effect of LY117018 on uterus weight and luciferase activity was modest and significantly lower than the effect of OE 2 . LY117018 and OE 2 treatment resulted in similar luciferase activation in thymus. However, only OE 2 treatment resulted in thymic atrophy, while no effect on thymus weight was seen after LY117018 treatment. In summary, the raloxifene analogue LY117018 can activate the classical oestrogen pathway in bone, uterus and thymus in vivo, and this activation is associated with BMD and uterus weight, but not thymus weight.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Engdahl

Jochéms

Gustafsson

et al. 2009

Journal of Endocrinology

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“…RANKL is produced by osteoblastic lineage cells, and activated T cells promotes osteoclast formation, fusion, differentiation, activation, and survival, leading to enhanced bone resorption and bone loss. RANKL expression is modulated by various cytokines (IL-1, IL-6, IL-11), glucocorticoids, and PTH [26,38]. It is known that oestrogens inhibit RANKL production, diminishing bone resorption [25].…”

Section: Discussionmentioning

confidence: 99%

“…Although oestrogens do not constitute an etiological factor of AIS, they can influence the progression of spinal deformation, interacting with other factors modulating growth, biomechanics, and the structure of bones. Oestrogens repress osteoclastogenic cytokine production, including interleukine-6 (IL-6), interleukine-1 (IL-1), receptor activator of nuclear factor B ligand (RANKL) from immune cells and osteoblasts, increase osteoblast proliferation, decrease osteoblast and osteocyte apoptosis and induce osteoclast apoptosis [25,26]. As scoliosis is frequently concomitant to decreased concentrations of oestrogens and delayed puberty, it has been hypothesized that oestrogen deficiency can play an important role in the multifactorial pathomechanism of AIS [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Participation of sex hormones in multifactorial pathogenesis of adolescent idiopathic scoliosis

Kulis

Goździalska

Drąg

et al. 2015

International Orthopaedics (SICOT)

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Purpose In order to verify the potential association between the aetiopathogenesis of adolescent idiopathic scoliosis (AIS) and the process of sexual maturation, we determined the concentrations of oestrogens in pre-and postmenarcheal girls affected by this condition. AIS, occurring mostly in pubescent girls, is one of the most frequent forms of faulty posture. Therefore, it was assumed that the multifactorial pathomechanism of AIS involves significant deficiency of oestrogens. Methods The diagnosis of AIS was established on the basis of physical examination and analyses of radiograms. Concentrations of FSH, LH, oestrogens, progesterone, osteocalcin and RANKL were determined by ELISA. The activity of alkaline phosphatase (AP) was measured by kinetic method. The study included pre-and postmenarcheal girls with AIS and corresponding groups of scoliosis-free controls. Results In premenarcheal scoliotic girls, the levels of FSH, LH and oestradiol were lower; the levels of progesterone, oestrone and oestriol were higher; and the concentrations of oestrone and oestriol were similar compared to premenarcheal controls. Higher levels of RANKL, osteocalcin and AP were observed in premenarcheal adolescents with AIS compared to controls. The concentrations of FSH, LH, oestradiol, and progesterone in postmenarcheal girls with scoliosis were lower, oestrone were slightly lower and oestriol did not differ compared with the control group. Significantly higher levels of RANKL, osteoc alcin an d A P w ere o bserv ed i n postmenarcheal scoliotic adolescents compared with controls. Conclusions There is an interdependence between the concentration of oestradiol and development of scoliosis. Determination of estradiol may have diagnostic value in the screening of spinal pathologies associated with AIS.

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“…OPG acts as an endogenous inhibitor of osteoclast differentiation and activation by binding to RANKL, and thus neutralizing and preventing its binding to the specific receptor RANK expressed on osteoclasts and their precursors (Hofbauer et al 2000), resulting in decreased osteoclastogenesis and osteoclast function. Several hormones, growth factors, cytokines, and prostaglandins regulate the OPG/RANKL/RANK system through their direct effects on bone cells (Cheung et al 2003, Suda et al 2004. Even GH appears to modulate this system, since GH replacement therapy enhances OPG levels both in blood (Lanzi et al 2003) and in trabecular and cortical bone explants from GHdeficient patients (Ueland et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells

Mrak

Villa²,

Lanzi

et al. 2007

Journal of Endocrinology

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It is presently thought that osteoprotegerin (OPG) is a cytokine involved in the regulation of osteoblast/osteoclast crosstalk and maintenance of bone mass. Recent studies showed that GH replacement therapy in GH-deficient patients was able to induce a significant increase of OPG in the plasma, as well as in the cortical and the trabecular bone. In order to determine whether GH could directly modulate OPG secretion, the effect of GH on human osteoblast-like cells (hOB) in primary culture was studied. After detecting the presence of the mRNA for the GH receptor (GHR) by RT-PCR, hOB were exposed to increasing concentrations of GH, from 0 . 1 to 25 ng/ml, for 24 h. The results showed that GH exposure was able to stimulate OPG secretion in a concentration-dependent manner. In addition, the OPG mRNA levels were increased, indicating that the hormone has a stimulatory effect on gene expression. The stimulatory effect on OPG expression and production was prevented by exposing the cells to tyrphostin AG490 (10 mM), an inhibitor of Janus kinase 2, which is one of the kinases involved in the intracellular pathway activated by the binding of GH to its receptor. Similar results were obtained when the cells were exposed to a receptor antagonist of GH, pegvisomant at 50 nM. GH exposure neither induced an increase in IGF-I expression nor secretion in hOB. These results suggest that the stimulation of OPG production induced by GH in hOB is specific and receptor mediated and further support the view that GH is able to modulate bone remodeling by directly influencing osteoblast-osteoclast crosstalk.

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Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene

Cited by 74 publications

References 40 publications

In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Participation of sex hormones in multifactorial pathogenesis of adolescent idiopathic scoliosis

Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells

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