Die molekularen Wirkmechanismen des Glukokortikoidrezeptors bei der Glukokortikoid-induzierten Osteoporose

Zusammenfassung

Die Glukokortikoid-induzierte Osteoporose (GIO) ist die häufigste Form der sekundären Osteoporose. Die molekularen Wirkmechanismen, über die Glukokortikoide (GC) zum Verlust von Knochenmasse führen, waren lange Zeit nicht bekannt. Genomweite Studien zum Glukokortikoidrezeptor (GR) sowie zellspezifische und funktionale Deletionen haben jedoch unser Verständnis von GC-Wirkmechanismen im Knochen revolutioniert. Der GR reguliert Genexpression als Ein zel-(Monomer) und Doppel-Molekül (Dimer) durch direkte und indirekte DNA-Bindung. Inzwischen ist funktionell erwiesen, dass vor allem direkte Effekte auf Osteoklasten, Osteoblasten und Osteozyten entscheidend sind. Hauptsächlich die Beeinträchtigung von Osteoblasten führt in der GIO zum Knochenschwund. Dies geschieht durch eine gesteigerte Apoptose, vermindertes Wachstum und vor allem gestörte Differenzierung von mesenchymalen Stammzellen. In hohen Dosen hemmen GC pro-osteogene Signalwege, wie etwa Wnt-Signale. GR-Monomer-abhängige Genexpression scheint hierbei maßgebend zu sein. Aktuelle Herausforderungen in der GIO-Forschung sind das Verständnis der physiologischen, anabolen GC-Funktion, die genaue Definition von Differenzierungsstadien, die sensibel auf pharmakologisch-dosierte GC reagieren, sowie die Identifizierung von neuen Zielstrukturen, die es erlauben, die knochenschä-digenden Wirkungen von GC zu überwinden.

Summary

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteo -porosis. As glucocorticoids (GC) act on most tissues, the cellular and molecular mechanisms of GC induced bone loss were not known for a long time. Genome wide studies of DNA binding by the GC receptor, the GR, and cell-type specific and function-selective deletions of the GR have recently revolutionized our understanding of GC action in bone. After nuclear translocation the GR regulates gene expression by binding as a monomer or dimer directly or indirectly to DNA. There are now multiple lines of evidence that GC actions on bone are mainly mediated directly by the bone cells i. e. osteoclasts, osteoblasts and osteocytes. GC treatment can induce osteoclast activity and cause high rates of bone resorption but the effect of GR signaling on os teoclast development and function still remains controversial. Osteocytes have been shown to be very sensitive to GC-induced apoptosis. Nonetheless, the major cause of bone loss in GIO appears to be the impairment of osteoblast function which in fact takes place at several levels. GC induce apoptosis and inhibit osteoblast proliferation. Most importantly they also inhibit the differentiation of osteoblasts from mesenchymal progenitor cells. GC lead to the enhancement of adipogenesis at the cost of osteoblast development. Whether this takes place at the same level of progenitor cells still remains to be elucidated, however. High dose GC exposure of bone cells leads to interference with pro-osteogenic signaling, such as the Wnt pathway. GR monomer-dependent gene expression programs seem to be decisive here. miRNAs have also been shown to influence the bone integrity but at least in GIO they appear to play a minor role. Despite substantial progress of understanding molecular mechanisms underlying GIO, some questions remain unanswered. Current challenges in GIO research are i) the understanding of physiological anabolic effects of low dose GCs, ii) the clear definition of the osteoblast and osteoclast differentiation stages that are vul nerable to pharmacological GCs in vivo and iii) the identification of novel drug targets, enhancing osteoblast function to overcome the deleterious effects of GCs on bone. Novel high-throughput screening methods for primary cells and facilitated genetic manipulation for rodent models offer a promising outlook for this challenging task.

Schlüsselwörter

Glukokortikoidrezeptor - Glukokortikoid-induzierte Osteoporose - Osteoblast - Osteoklast - Osteozyt

Keywords

Glucocorticoid receptor - glucocorticoid-induced osteoporosis - osteoblast - osteoclast - osteocyte

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