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Open Access Research article

Role of hypoxia-inducible factor 1alpha in the integrity of articular cartilage in murine knee joints

Kolja Gelse123*, David Pfander4, Simon Obier1, Karl X Knaup3, Michael Wiesener3, Friedrich F Hennig2 and Bernd Swoboda1

Author Affiliations

1 Division of Orthopaedic Rheumatology, University of Erlangen-Nuremberg, Rathsberger Straße 57, Erlangen 91054, Germany

2 Department of Orthopaedic Trauma Surgery, University Hospital Erlangen, Krankenhausstraße 12, Erlangen 91054, Germany

3 Interdisciplinary Center for Clinical Research, University Hospital Erlangen, Glückstraße 6, Erlangen 91054, Germany

4 Division of Orthopaedic Rheumatology, Hufeland-Clinic, Langensalzaer Landstraße 1, Muehlhausen 99974, Germany

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Arthritis Research & Therapy 2008, 10:R111  doi:10.1186/ar2508

Published: 12 September 2008

Abstract

Introduction

Chondrocytes have to withstand considerable hypoxic conditions within the avascular articular cartilage. The present study investigated the effects of inhibiting or stabilizing hypoxia-inducible factor (HIF)-1α by 2-methoxyestradiol or dimethyloxaloylglycine on the progression of osteoarthritis in murine knee joints.

Methods

2-Methoxyestradiol was injected six times over a period of 2 weeks into the left knee joint of Balb/C mice. Joints were assessed by histochemical and immunohistochemical methods, 3 weeks and 12 weeks following the first injection. Dimethyloxaloylglycine, an inhibitor of HIF-degrading prolyl-hydroxylases, was injected into the left knee joints of STR/ORT mice once a week over the entire period of 12 weeks. Right knee joints that received a saline solution served as controls. In addition, the effects of dimethyloxaloylglycine on HIF-1 target gene expression and on collagen metabolism were analyzed in vitro.

Results

Injection of 2-methoxyestradiol led to osteoarthritic changes in the treated knee joints of Balb/C mice. The first signs of osteophyte formation were observed in the knee joints after 3 weeks, followed by progressive destruction of the articular cartilage at 12 weeks that was not, however, accompanied by inflammatory reactions. Injection of dimethyloxaloylglycine could not prevent severe osteoarthritis that spontaneously developed in the knee joints of STR/ORT mice. In chondrocyte cultures, administration of dimethyloxaloylglycine resulted in an upregulation of Sox9 expression. Such a stimulatory effect was not observed, however, for the expression of type II collagen, which might be the indirect consequence of intracellular collagen retention observed by immunofluorescence or of increased expression of IL-1β and IL-6.

Conclusions

Induction of osteoarthritis by 2-methoxyestradiol demonstrates the importance of HIF-1 in maintaining the integrity of hypoxic articular cartilage. Stabilization of HIF-1 by dimethyloxaloylglycine, however, was not of therapeutic value, since this nonselective prolyl-hydroxylase inhibitor also interferes with proper collagen metabolism and induces the expression of catabolic cytokines