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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-25520

Kurowska-Stolarska, M; Distler, J H; Jüngel, A; Rudnicka, W; Neumann, E; Pap, T; Wenger, R H; Michel, B A; Müller-Ladner, U; Gay, R E; Maslinski, W; Gay, S; Distler, O (2009). Inhibitor of DNA binding/differentiation 2 induced by hypoxia promotes synovial fibroblast-dependent osteoclastogenesis. Arthritis and Rheumatism, 60(12):3663-3675.

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OBJECTIVE: To map hypoxic areas in arthritic synovium and to establish the relevance of low oxygen levels to the phenotype of synovial fibroblasts, with special focus on bone degradation. METHODS: To analyze the distribution of hypoxia in arthritic joints, the hypoxia marker EF5 was administered to mice with collagen-induced arthritis (CIA). To evaluate the effect of hypoxia on rheumatoid arthritis synovial fibroblasts (RASFs), reverse suppression subtractive hybridization and complementary DNA array were used. Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to evaluate the expression of inhibitor of DNA binding/differentiation 2 (ID-2). To investigate the function of ID-2 in RASFs, cells were transfected either with ID-2 vector or with ID-2-specific small interfering RNA. RESULTS: EF5 staining showed the presence of hypoxia in arthritic joints, particularly at sites of synovial invasion into bone. Differential expression analysis revealed that ID-2 was strongly induced by hypoxia in RASFs. Immunohistochemical analysis of CIA mouse synovium and human RA synovium showed a strong expression of ID-2 by RASFs at sites of synovial invasion into bone. Overexpression of ID-2 in RASFs significantly induced the expression of several factors promoting osteoclastogenesis. The biologic relevance of the potent osteoclastogenesis-promoting effects was shown by coculture assays of ID-2-overexpressing RASFs with bone marrow cells, leading to an increased differentiation of osteoclasts from bone marrow precursors. CONCLUSION: The data show that hypoxic conditions are present at sites of inflammation and synovial invasion into bone in arthritic synovium. Hypoxia-induced ID-2 may contribute to joint destruction in RA patients by promoting synovial fibroblast-dependent osteoclastogenesis.


8 citations in Web of Science®
9 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Deposited On:14 Dec 2009 08:21
Last Modified:05 Apr 2016 13:37
Funders:Zurich Center for Integrative Human Physiology, Hartmann-Müller Foundation, Zürich, Switzerland, A Career Support Award of Medicine from the Ernst Jung Foundation (Dr. Distler's work), DFG Grant (Dr. Distler's work), European Community (Dr. Jüngel's work), DFG Grant (Dr. Müller-Ladner's work)
Additional Information:The definitive version is available at www.blackwell-synergy.com
Publisher DOI:10.1002/art.25001
PubMed ID:19950294

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