The Immunosuppressant FTY720 (fingolimod) Enhances Glycosaminoglycan Depletion in Articular Cartilage

Overview

Journal BMC Musculoskelet Disord

Publisher Biomed Central

Specialties Orthopedics
Physiology

Date 2011 Dec 14

PMID 22151889

Citations 4

Authors

Martin H Stradner

Hannes Angerer

Thomas Ortner

Florentine C Fuerst

Daniela Setznagl

Marie-Luise Kremser

Josef Hermann

Winfried B Graninger

Affiliations

Soon will be listed here.

Abstract

Background: FTY720 (Fingolimod) is a novel immunosuppressive drug investigated in clinical trials for organ transplantation and multiple sclerosis. It acts as a functional sphingosine-1-phosphate (S1P) receptor antagonist, thereby inhibiting the egress of lymphocytes from secondary lymphoid organs. As S1P is able to prevent IL-1beta induced cartilage degradation, we examined the direct impact of FTY720 on cytokine induced cartilage destruction.

Methods: Bovine chondrocytes were treated with the bioactive phosphorylated form of FTY720 (FTY720-P) in combination with IL-1beta or TNF-alpha. Expression of MMP-1,-3.-13, iNOS and ADAMTS-4,-5 and COX-2 was evaluated using quantitative real-time PCR and western blot. Glycosaminoglycan depletion from cartilage explants was determined using a 1,9-dimethylene blue assay and safranin O staining.

Results: FTY720-P significantly reduced IL-1beta and TNF-alpha induced expression of iNOS. In contrast FTY720-P increased MMP-3 and ADAMTS-5 mRNA expression. Furthermore depletion of glycosaminoglycan from cartilage explants by IL-1beta and TNF-alpha was significantly enhanced by FTY720-P in an MMP-3 dependent manner.

Conclusions: Our results suggest that FTY720 may enhance cartilage degradation in pro-inflammatory environment.

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Veronesi F, Fini M, Giavaresi G, Ongaro A, De Mattei M, Pellati A BMC Musculoskelet Disord. 2015; 16:308.

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Ahn M, Jee S, Hwang J, Yun E, Ahn K, Kim Y Toxicol Res. 2014; 29(3):195-201.

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Sphingosine 1-phosphate counteracts the effects of interleukin-1β in human chondrocytes.

Stradner M, Gruber G, Angerer H, Huber V, Setznagl D, Kremser M Arthritis Rheum. 2013; 65(8):2113-22.

PMID: 23666803 PMC: 3763206. DOI: 10.1002/art.37989.

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