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Potential of resveratrol analogues as antagonists of osteoclasts and promoters of osteoblasts.

Kupisiewicz K, Boissy P, Abdallah BM, Hansen FD, Erben RG, Savouret JF, Søe K, Andersen TL, Plesner T, Delaisse JM - Calcif. Tissue Int. (2010)

Bottom Line: The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected.Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling.However, further studies are required to establish their efficacy in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Clinical Cell Biology, Vejle Hospital, IRS/CSFU, University of Southern Denmark, Vejle, Denmark. kkupisiewicz@health.sdu.dk

ABSTRACT
The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo.

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Effect of RSV and its analogues on RANKL-mediated NF-κB activation and NFATc1 expression in differentiating OCs. One-hour or 7-day treatment with PDM02 suppressed RANKL-induced nuclear translocation of NF-κB (a). Total numbers of cells counted are given above in parenthese for each condition. Effect of PDM02, PDM10, PDM11, and RSV (100 μM) on NFATc1 gene expression in differentiating OCs after 1 hour or 7-day treatment with analogues and RANKL (b). Each bar is the mean ± SD value relative to human GUS and ABL of three cultures. * P < 0.05, ** P < 0.01, *** P < 0.001 statistically significant effect of PDM02 compared to cells cultured without analogues. Results are representative of two independent experiments
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Fig4: Effect of RSV and its analogues on RANKL-mediated NF-κB activation and NFATc1 expression in differentiating OCs. One-hour or 7-day treatment with PDM02 suppressed RANKL-induced nuclear translocation of NF-κB (a). Total numbers of cells counted are given above in parenthese for each condition. Effect of PDM02, PDM10, PDM11, and RSV (100 μM) on NFATc1 gene expression in differentiating OCs after 1 hour or 7-day treatment with analogues and RANKL (b). Each bar is the mean ± SD value relative to human GUS and ABL of three cultures. * P < 0.05, ** P < 0.01, *** P < 0.001 statistically significant effect of PDM02 compared to cells cultured without analogues. Results are representative of two independent experiments

Mentions: Stimulation of RANK during OC differentiation results in NF-κB activation followed by induction of NFATc1 expression. We assessed the effect of RSV analogues on NF-κB activation during OC differentiation by assaying the nuclear translocation of its p65 component (Fig. 4). As expected, transient stimulation with rhRANKL increased the number of cells with p65 in the nucleus compared to the cultures treated with rhM-CSF alone (Fig. 4a). Pretreatment for 1 h or 7 days with PDM02 abrogated the rhRANKL-triggered translocation of p65 to the nucleus and activation of NF-κB even at low doses (Fig. 4a). Note for comparison that 1-h pretreatment with RSV prior to adding rhRANKL was not sufficient to prevent the nuclear translocation of NF-κB, whereas 7-day treatment resulted in an inhibitory effect as previously reported [10].Fig. 4


Potential of resveratrol analogues as antagonists of osteoclasts and promoters of osteoblasts.

Kupisiewicz K, Boissy P, Abdallah BM, Hansen FD, Erben RG, Savouret JF, Søe K, Andersen TL, Plesner T, Delaisse JM - Calcif. Tissue Int. (2010)

Effect of RSV and its analogues on RANKL-mediated NF-κB activation and NFATc1 expression in differentiating OCs. One-hour or 7-day treatment with PDM02 suppressed RANKL-induced nuclear translocation of NF-κB (a). Total numbers of cells counted are given above in parenthese for each condition. Effect of PDM02, PDM10, PDM11, and RSV (100 μM) on NFATc1 gene expression in differentiating OCs after 1 hour or 7-day treatment with analogues and RANKL (b). Each bar is the mean ± SD value relative to human GUS and ABL of three cultures. * P < 0.05, ** P < 0.01, *** P < 0.001 statistically significant effect of PDM02 compared to cells cultured without analogues. Results are representative of two independent experiments
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2964465&req=5

Fig4: Effect of RSV and its analogues on RANKL-mediated NF-κB activation and NFATc1 expression in differentiating OCs. One-hour or 7-day treatment with PDM02 suppressed RANKL-induced nuclear translocation of NF-κB (a). Total numbers of cells counted are given above in parenthese for each condition. Effect of PDM02, PDM10, PDM11, and RSV (100 μM) on NFATc1 gene expression in differentiating OCs after 1 hour or 7-day treatment with analogues and RANKL (b). Each bar is the mean ± SD value relative to human GUS and ABL of three cultures. * P < 0.05, ** P < 0.01, *** P < 0.001 statistically significant effect of PDM02 compared to cells cultured without analogues. Results are representative of two independent experiments
Mentions: Stimulation of RANK during OC differentiation results in NF-κB activation followed by induction of NFATc1 expression. We assessed the effect of RSV analogues on NF-κB activation during OC differentiation by assaying the nuclear translocation of its p65 component (Fig. 4). As expected, transient stimulation with rhRANKL increased the number of cells with p65 in the nucleus compared to the cultures treated with rhM-CSF alone (Fig. 4a). Pretreatment for 1 h or 7 days with PDM02 abrogated the rhRANKL-triggered translocation of p65 to the nucleus and activation of NF-κB even at low doses (Fig. 4a). Note for comparison that 1-h pretreatment with RSV prior to adding rhRANKL was not sufficient to prevent the nuclear translocation of NF-κB, whereas 7-day treatment resulted in an inhibitory effect as previously reported [10].Fig. 4

Bottom Line: The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected.Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling.However, further studies are required to establish their efficacy in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Clinical Cell Biology, Vejle Hospital, IRS/CSFU, University of Southern Denmark, Vejle, Denmark. kkupisiewicz@health.sdu.dk

ABSTRACT
The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo.

Show MeSH
Related in: MedlinePlus