Zusammenfassung
Selektive Östrogen Rezeptor Modulatoren wirken auf verschiedene Gewebe durch Östrogen Rezeptoren und bewirken fördernde oder hemmende Effekte bei der Entstehung von Osteoporose. Ziel dieser Studie ist die Wirkung des Östrogen Rezeptor Modulators LY 117018, einem Raloxifen Analog, auf die Osteoklastogenese zu untersuchen. In primären Knochenmarkszellkulturen von Mäusen wurden Osteoklasten, definiert als TRAP-positive mehrkernige Zellen, mit 10–8 M 1,25-dihydroxy Vitamin D3 induziert. 10–12 M bis 10–9 M LY117018 reduzierte die Anzahl der Osteoklasten. Höhere Konzentrationen hatten keinen Effekt auf die Generation der Osteoklasten. LY117018 steigerte die Alkaline Phosphatase Aktivität von Maus Kalvarien Osteoblasten in einer Konzentration von 10–14 M bis 10–7 M, aber hatten keinen Einfluss auf die Proliferation und Transkription von RANKL und Osteoprotegerin. Mäusemilzzellen wurden mit LY117018 inkubiert um die Produktion von Knochenresorbierenden Zytokinen zu messen. Die Daten von vier Flow Zytometrie Analysen zeigten eine signifikant reduzierte Frequenz der Tumor Nekrose Faktor-α positiven CD8+ Zellen nach Behandlung mit LY117018. Die Untersuchung zeigt, dass LY117018 signifikant die Generation der Osteoklasten hemmt und gleichzeitig die osteogene Differenzierung von Osteoblasten in vitro stimuliert. Die Verminderung der Tumor Nekrose Faktor-α Produktion durch LY117018 könnte zu seinem anti-osteoklastären Effekt beitragen.
Summary
Selective estrogen receptor modulators are compounds that act via estrogen receptors in different tissues to mediate either estrogenic or estrogen antagonistic effects in osteoporosis patients. The aim of this study was to assess the effect of the selective estrogen receptor modulator LY117018, a raloxifene analogue, on osteoclastogenesis in vitro. In primary murine bone marrow cultures osteoclasts, defined as TRAP-positive multinucleated cells, were induced by 10–8 M 1,25-dihydroxyvitamin D3. LY117018 at concentrations between 10–12 M and 10–9 M significantly reduced the number of osteoclasts. At higher concentrations no effect of LY117018 on osteoclast generation was observed. LY117018 enhanced alkaline phosphatase activity of mouse calvaria osteoblasts at a concentration of 10–14 to 10–7 M, but had no influence on the proliferation and transcription of RANKL and osteoprotegerin. In order to study the effect of the compound on the production of cytokines that can stimulate bone resorption, spleen cells were incubated with LY117018. Data from four-color flow cytometric analysis indicate a significantly decreased frequency of tumor necrosis factor-α positive CD8+ cells after treatment with LY117018. These findings suggest that LY117018 can significantly inhibit the generation of osteoclasts and stimulate osteogenic differentiation in vitro. Suppression of tumor necrosis factor-α production by LY117018 may contribute to its anti-osteoclastogenic effect.
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Wutzl, A., Gruber, R., Brozek, W. et al. Mechanisms involved in the inhibition of osteoclast generation by the benzothiophene SERM LY117018. Wien Klin Wochenschr 122, 626–632 (2010). https://doi.org/10.1007/s00508-010-1469-z
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DOI: https://doi.org/10.1007/s00508-010-1469-z