Upregulated hypoxia inducible factor-1α and -2α pathway in rheumatoid arthritis and osteoarthritis

Arthritis Research & Therapy

Alexandra Giatromanolaki⁴  Efthimios Sivridis⁴  Efstratios Maltezos¹  Nick Athanassou³  Dimitrios Papazoglou¹  Kevin C Gatter³  Adrian L Harris²  Michael I Koukourakis⁵ 

[1] Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece

[2] Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

[3] Department of Pathology, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK

[4] Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece

[5] Department of Radiotherapy/Oncology Democritus University of Thrace, Alexandroupolis, Greece

关键词: VEGF;    thymidine phosphorylase;    rheumatoid arthritis;    osteoarthritis;    hypoxia inducible factors;   

Others  :  1101374
DOI  :  10.1186/ar756

 received in 2002-12-20, accepted in 2003-03-10,  发布年份 2003

【 摘 要 】

The pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA) remains obscure, although angiogenesis appears to play an important role. We recently confirmed an overexpression of two angiogenic factors, namely vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF), by the lining and stromal cells of the synovium in both conditions. Because hypoxia inducible factor (HIF)-1α and HIF-2α are essential in regulating transcription of the VEGF gene, active participation of HIF-α molecules in the pathogenesis of these arthritides is anticipated. We investigated the immunohistochemical expression of HIF-1α and HIF-2α in the synovium of 22 patients with RA, 34 patients with OA and 22 'normal' nonarthritic individuals, in relation to VEGF, VEGF/KDR (kinase insert domain protein receptor) vascular activation, PD-ECGF and bcl-2. A significant cytoplasmic and nuclear overexpression of HIF-1α and HIF-2α was noted in the synovial lining and stromal cells of both diseases relative to normal. Overexpression of HIF-αs was related to high microvessel density, high PD-ECGF expression and high VEGF/KDR receptor activation, suggesting HIF-α-dependent synovial angiogenesis in OA. By contrast, the activation of the angiogenic VEGF/KDR pathway was persistently increased in RA, as indeed was microvessel density and the expression of PD-ECGF, irrespective of the extent of HIF-α expression, indicating a cytokine-dependent angiogenesis. In all cases, the VEGF/KDR vascular activation was significantly lower in OA than in RA, suggesting a relative failure of the HIF-α pathway to effectively produce a viable vasculature for OA, which is consistent with the degenerative nature of the disease. The activation of the HIF-α pathway occurs in both RA and OA, although for unrelated reasons.

【 授权许可】

   
2003 Giatromanolaki et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

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