Sexualsteroide in der Homöostase des Knochens

Zusammenfassung

Die Sexualhormone Östradiol und Dihydrotestosteron spielen eine herausragende Rolle für die Entwicklung, das Wachstum und die Regeneration des Knochens. Molekulare Grundlage der Wirkung von Sexualhormonen auf den Knochen ist die Expression spezifischer Rezep - torproteine in Knochenzellen selbst und in Organen, die den Knochen beeinflussen. Neben den klassischen Östrogenrezeptoren (ER) und Androgenrezeptoren (AR) gibt es auch membranassoziierte Rezeptoren wie den kürzlich entdeckten G-Protein-gekoppelten Rezeptor 30 (GPR30, GPER), der ebenfalls Östrogene bindet. Sexualhormone sind pleiotrop, direkte und indirekte Auswirkungen von Sexualhormonen auf die Knochenhomöostase sind jedoch oft schwer voneinander zu trennen. Zudem können Knochenzellen selbst Sexualhormone aktivieren oder abbauen, indem sie Enzyme des Steroid-Metabolismus exprimieren. Testo - steron ist das Vorläufer steroid für beide Sexualhormone und kann durch die beiden Schlüsselenzyme Aromatase und 5⟨-Reduktase jeweils in Östradiol oder 5α-Dihydrotestosteron umgewandelt werden. Die vielfältigen Ebenen der Regulation lassen sich für die klinische Praxis so zusammenfassen, dass ihre Hauptwirkung darin besteht, die Anzahl und die Aktivität von Osteoklasten zu regulieren und die Knochenformation zu unterstützen. Der Verlust von Sexualhormonen bedingt Knochenverlust durch gesteigerten Abbau. Dies wird durch Beeinflussung des OPG/RANKL-Quotienten erreicht (AR und ER) und durch Regulation der Produktion des Apoptose-induzierenden Fas-Liganden in Osteoklasten (ER). Sexualhormone unterstützen die Knochenformation auf vielen Ebenen, vor allem fördern Östrogene die Mechanosensitivität. Für die Prävention und Therapie des Knochenverlusts ergeben sich daher unverändert therapeutische Perspektiven durch die Entwicklung von selektiven Rezeptormodulatoren für beide Rezeptorsysteme (SERMs und SARMs). Auch die lokale Hormonaktivierung im Knochen kann zukünftig Ziel therapeutischer Maßnahmen werden, sei es durch die einfache Gabe von Steroidhormonvorläufern, die lokal gewebespezifisch aktiviert werden, oder durch Kleinmoleküle, die das Muster des lokalen Steroidmetabolismus modulieren.

Summary

Estradiol and dihydrotestosterone, the principal hormonal sex steroids, are important for the development, growth and regeneration of bone. The expression of the respective receptor proteins in bone cells and in the organs which influence bone homeostasis represents the molecular basis for sex steroid effects on bone. In addition to the classical estrogen receptors (ER) and androgen receptors (AR), which act as transcription factors, also membrane-associated receptors have been characterized, like the recently discovered estrogen binding G-protein coupled receptor 30 (GPR30, GPER). Due to the pleio tropic actions of sex hormones it is difficult to dissect their direct and indirect effects on bone homeostasis. Moreover, bone cells themselves can activate or metabolize sex steroids by expressing the respective enzymes of steroid metabolism. Testosterone is a precursor for both sex steroids and can be converted into estradiol or 5α-dihydrotestosterone by the key activating enzymes aromatase and 5α-reductase respectively. The multifaceted levels of regulation can be summarised for clinical practice as two main effects of sex steroids on bone, which are to regulate the number and activity of osteoclasts and to support bone formation by osteoblasts. Loss of sex steroid activity causes bone loss, which is mediated by negatively influencing the OPG/RANKL ratio (ER and AR) and by up-regulation of the expression of the apoptosis inducing Fas-ligand in both osteoblasts and osteoclasts (ER). Sex steroids facilitate bone formation on multiple levels, the most important of which may be the mechanosensitizing effect of estradiol and ERα. Hence the field of sex steroids still provides promising targets for the development of therapeutic strategies in the prevention and therapy of bone loss, such as the development of selective receptor modulators for ER and AR (SERMs and SARMs). Local steroid metabolism in bone cells can also be used and targeted in future, e. g. by simply adding steroid hormone precursors which are locally activated in a tissue-specific manner, or by stimulating the local expression of steroid metabolizing enzymes to create a favourable steroid microenvironment.

Schlüsselwörter

Sexualhormone - Östrogenrezeptoren - Androgenrezeptoren - SERMs - SARMs

Keywords

Sex steroids - estrogen receptors - androgen receptors - SERMs - SARMs

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