Bedeutung des RANK/RANKL/OPGSignalwegs für den Knochenstoffwechsel

Zusammenfassung

Die meisten Knochenstoffwechselkrankheiten sind nach heutigem Kenntnisstand Folge einer gesteigerten Knochenresorption durch Osteoklasten. In den letzten 15 Jahren wurden die entscheidenden molekularen und zellulären Regulatoren der Zellbiologie von Osteoklasten entschlüsselt. Receptor activator of NF-κB-Ligand (RANKL) und sein Rezeptor RANK sind essenziell für die Differenzierung und Aktivierung von Osteoklasten und für eine normale Knochenresorption absolut erforderlich. Die Wirkungen von RANKL werden durch den endogenen löslichen Rezeptorantagonisten Osteoprotegerin (OPG) neutralisiert. Die Balance zwischen RANKL und OPG ist im Östrogenmangel oder bei systemischer Glukokortikoidtherapie gestört und dadurch wird der RANKL/OPG-Quotient erhöht, was zum beschleunigten Knochenverlust führt. Angesichts der fundamentalen Rolle des RANKL/RANK/OPG-Signalwegs im Knochenstoffwechsel ist mittlerweile RANKL zum therapeutischen Target geworden. Strategien der RANKL-Blockade wurden in verschiedenen Tiermodellen klinisch relevanter Knochenerkrankungen erfolgreich eingesetzt. Dazu zählen verschiedene Osteoporoseformen sowie Knochenverlust infolge systemischer Entzündung und Tumoren.

Summary

The majority of metabolic bone diseases is due to an enhanced bone resorption by osteoclasts. Over the last 15 years, the critical molecular and cellular pathways of osteoclast biology have been unravelled. Receptor activator of NF-κB ligand (RANKL) and its receptor RANK have been identified as the key mechanisms required for osteoclast differentiation and activation and to be undispensible for bone resorption. The effects of RANKL are counteracted by the endogenous decoy receptor osteoprotegerin (OPG). The critical balance between RANKL and OPG is disturbed in situations of estrogen deficiency or systemic glucocorticoid therapy, where the RANKL/OPG ratio is enhanced and associated with exaggerated bone loss. In light of the fundamental role of the RANKL/RANK/OPG pathway in bone remodelling, RANKL has become a therapeutic target. Strategies of RANKL blockade have been sucessfully employed in several animal models of bone loss conditions, including osteoporosis, bone loss associated with systemic inflammation, and cancer-related bone loss.

Schlüsselwörter

Knochenresorption - Osteoklast - RANKL - RANK

Keywords

Bone resorption - osteoclasts - RANKL - RANK

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