Signalwege der Östrogenrezeptoren in Knochenzellen

Zusammenfassung

Östradiol (E2) ist wichtig für die Regulierung des Knochenmetabolismus – nicht nur bei Frauen, sondern auch bei Männern. Auf der zellulären und molekularen Ebene werden die Effekte von E2 durch Östrogenrezeptoren (ERs) vermittelt. Verschiedene Signalwege sind in den vergangenen Jahren identifiziert worden, die alle eine wichtige Rolle in der Aufrechterhaltung der Knochenstruktur und Knochendichte spielen. ERs vermitteln die Effekte von E2 durch genomische (klassischer und nichtklassischer) und nichtgenomische Signalwege. Die Expression oder Repression von E2-Zielgenen wird des Weiteren durch die Bindung von Koregulatoren (Aktivatoren und Repressoren) an die Rezeptoren reguliert. Steroidrezeptor Koaktivatoren (SRCs) interagieren mit dem ligandengebundenen Zellkernrezeptordimer und dienen als Bindungsoberfläche für Transkriptionsfaktoren. Die Bildung dieses Transkriptionskomplexes ermöglicht eine optimale Transkription von steroidhormonenregulierten Zielgenen. Die Präsenz der ERs sowohl in Osteoblasten, Osteozyten und Osteoklasten beeinflusst die Knochenumgestaltung und Knochenresorption. Die Lebenslänge und die Einleitung der Apoptose der verschiedenen Zelltypen wird durch die Verfügbarkeit von E2 und die genaue Regulierung der verschiedenen Östrogensignalwegen und die Balance von Rezeptoren, Koaktivator und Korepressor Proteinen bestimmt.

Summary

Estradiol (E2) plays a major role in the regulation of bone turnover not only in females, but also in males. At the cellular and molecular level the effects of E2 are mediated by estrogen receptors (ERs). A number of different signaling pathways have been identified in recent years to maintain bone structure and bone mineral density. ERs modulate gene transcription through either the genomic (classical and non-classical) or the non-genomic pathway. In addition, the expression and repression of E2 target genes is regulated through the binding of coregulator proteins (activators or repressors). Steroid receptor coactivators interact with the ligand-bound receptor dimer and recruit additional transcription factors. The formation of this transcription complex facilitates the optimal transcription of steroid hormone regulated target genes. Osteoblasts, osteocytes, and osteoclasts express both the estrogen receptor alpha and beta (ERα and ERβ). E2 has three fundamental effects on bone metabolism: 1) it inhibits the activation of bone remodeling and the initiation of new basic multicellular units (BMUs); 2) it inhibits differentiation and promotes apoptosis of osteoclasts, thereby reducing bone resorption; and 3) while E2 suppresses self-renewal of early mesenchymal progenitors, it promotes the commitment and differentiation and prevents apoptosis of osteoblastic cells, and thereby maintaining bone formation at the cellular level. It is now appreciated that not only the receptors but the relative balance of receptors, coactivator, and corepressor proteins is important for the regulation of bone.

Schlüsselwörter

Östrogenrezeptoren - genomischer Signalweg - nichtgenomischer Signalweg - Steroidrezeptor-Koaktivator

Keywords

Estrogen receptor - genomic signaling pathway - non-genomic pathway - steroid receptor coactivator

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