Activin-Antagonisten in der Therapie der Osteoporose

F. Jakob; B. Klotz; L. Seefried; R. Ebert

doi:10.1055/s-0037-1619996

Osteologie, Table of Contents

Osteologie 2011; 20(03): 217-221
DOI: 10.1055/s-0037-1619996

Knochenzellbiologie und Osteoporosetherapie

Schattauer GmbH

Activin-Antagonisten in der Therapie der Osteoporose

Activin antagonists for the treatment of osteoporosis

F. Jakob

¹Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg

,

B. Klotz

¹Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg

,

L. Seefried

¹Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg

,

R. Ebert

¹Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg

› Author Affiliations

Abstract

Zusammenfassung

Activin A ist ein Polypeptid mit vielfältigen biologischen Wirkungen auf die Regulation der Fertilität, die Pluripotenz und Differenzierung von Stammzellen, die Differenzierung von Neuronen, Inselzellen und Immunzellen und die Regulation des Stoffwechsels. Activin gehört zu den Liganden der Familie der TGFβ- Superfamilie. Die Activine A, B und C binden an die Typ-II-BMP-Rezeptoren (Activin-Rezeptor IIA [ActRIIA] und IIB [ActRIIB]) und rekrutieren spezifische Typ-I-Rezeptoren (activin receptor-like kinase 2 [ALK2], 4 [ALK4] und 7 ]ALK7]). Da der ActRIIB auch andere Faktoren wie z. B. Myostatin (GDF8) und die Bone Morphogenetic Proteins 7 und 2 (BMP-7, BMP-2) bindet, konkurrieren diese Liganden um den Rezeptor. Im Alter findet man erhöhte Activin- Spiegel im Serum. Activin-Antagonisten verändern die Balance zwischen den verschiedenen Liganden und verursachen eine veränderte Genregulation an allen Zellen, die entsprechende Signalsysteme exprimieren. Ein ACTIIIGG- Fusionsprotein mit Activin-antagonistischer Wirkung wird unter dem Namen Sotatercept (ACE-011) bereits klinisch als Medikament gegen die Tumor-induzierte und die Chemotherapie- induzierte Anämie erprobt und präklinisch für die Therapie der Osteoporose entwickelt. Am Knochen entfaltet der Antagonist eine duale Wirkung, er zeigt ausgeprägte anabole Effekte und verringert die Knochenresorption. In einem Mausmodell der Androgendefizienz werden zudem eine anabole Wirkung am Muskel und eine Verringerung des Fettgewebes beschrieben. Weitere Studien sind auf dem Weg, um sicherzustellen, dass das vielversprechende Medikament bei der Anwendung am Menschen neben der Effizienz auch ein gutes Sicherheits- und Nebenwirkungsprofil besitzt. Wenn es die Klinikreife erreicht, wird es unser therapeutisches Arsenal zur Behandlung der Osteoporose und möglicherweise auch der Sarkopenie wesentlich bereichern.

Summary

Activin A is a polypeptide displaying a diversity of biological effects such as regulation of fertility, pluripotency and differentiation of stem cells, differentiation of neuronal cells, pancreatic islet cells, immune cells and regulation of metabolism. Activins belong to the TGFβ superfamily of ligands. Activin A, B and C bind to specific type II receptors (activin-receptors IIA [ActRIIA] and IIB [ActRIIB]) thereby recruiting specific type I receptors (activin receptorlike kinase 2 [ALK2], 4 [ALK4] and 7 [ALK7]). ActRIIB may also bind other factors like myostatin (GDF8) and the bone morphogenetic proteins 7 and 2 (BMP-7, BMP-2), hence these ligands compete for the binding sites. Serum activin levels are elevated in the elderly. Activin antagonists modify the balance between the diversity of ligands thereby changing gene expression in tissues responsive to the respective signal transduction systems. An ACTII-IGG fusion protein, Sotatercept (ACE-011), displaying activin ant agonistic efficacy, is already clinically developed as a treatment for tumor- and chemotherapy-associated anemia and is also in preclinical development for the treatment of osteoporosis. This antagonist exerts dual effects in bone in that it displays both strong anabolic efficacy combined with antiresorptive effects. Moreover, in a mouse model of androgen deficiency marked muscle anabolic effects have been demonstrated as well as a reduction of adipose tissue. Future studies will have to show that its profile of safety and side effects allows applications in the human setting. If it will reach the clinical stage it will represent a promising additional strategy to treat osteoporosis and sarcopenia in the elderly.

Schlüsselwörter

Osteoporose - Activin - Activin-Antagonisten - TGFβ-Superfamilie

Keywords

Osteoporosis - Activin - Activin antagonists - TGFβ superfamily

Full Text

References

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