Die Rolle der Wnt-Inhibitoren Sklerostin und Dickkopf-1 bei Erkrankungen des Knochens^[*]

Zusammenfassung

Knochen wird durch die koordinierte Aktivität von knochenresorbierenden Osteoklasten sowie von Osteoblasten, die neue Knochenmatrix produzieren, kontinuierlich umgebaut. Ein gestörtes Gleichgewicht zwischen beiden Zelltypen stellt ein Leitmotiv vieler metabolischer Knochenerkrankungen dar. Hierbei fällt dem Wnt-Signalweg eine zentrale Bedeutung zu. Dieser fördert die Osteoblastogenese und wird durch die Wnt-Antagonisten Dickkopf-1 (DKK-1) und Sklerostin feinreguliert, da sie eine hemmende Wirkung auf die Osteoblasten-differenzierung entfalten. Beide Proteine sind zellbiologisch gut charakterisiert und lassen sich auch beim Menschen mithilfe sensitiver Assays nachweisen und als Biomarker bestimmen. Sowohl DKK-1 und Sklerostin werden in aktuellen präklinischen und klinischen Studien als therapeutische Ansatzpunkte für Erkrankungen des Knochens diskutiert, bei denen es zu einem Verlust von Knochengewebe und einem erhöhten Frakturrisiko kommt.

Summary

Bone undergoes continuous remodeling by the tightly coordinated activities of both bone resorbing osteoclasts as well as osteoblasts which produce new mineralized bone matrix. An imbalance of these cell types is a hallmark of numerous metabolic bone disorders. The Wnt pathway plays a key role in bone remodeling by promoting the differentiation of osteoblasts. Dickkopf-1 (DKK-1) and Sclerostin represent two potent inhibitors of the Wnt pathway thereby mediating a finetuning of osteoblastogenesis. The biological function of these proteins is well characterized and both are detectable as biomarkers in humans by sensitive assays. Current preclinical and clinical studies point to the potential therapeutic benefit by targeting DKK-1 and Sclerostin in bone disorders that are accompanied by the loss of bone mass and an increased fracture risk.

Schlüsselwörter

Sklerostin - Dickkopf-1 - Wnt-Signalweg - Osteoblasten - Osteoporose - Knochenmetastasen

Keywords

Sclerostin - Dickkopf-1 - Wnt pathway - osteoblasts - osteoporosis - bone metastases

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