Synovial Hypoxia as a Cause of Tendon Rupture in Rheumatoid Arthritis

Sivakumar, Branavan; Akhavani, Mohammed Ali; Winlove, C. Peter; Taylor, Peter; Paleolog, Ewa; Kang, Norbert

doi:10.1016/j.jhsa.2007.09.002

Cited by 94 publications

(103 citation statements)

References 36 publications

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“…RASF cultures under normoxia (with/without TNF-a) reduced exRNA secretion to nondetectable levels. Secretion of exRNA by RASF under hypoxia is in line with observations that hypoxia is a hallmark of inflamed RA joints (50). Significantly increased RNase levels in RA versus PsA synovial fluids were not detectable in cultured cells.…”

Section: Effect Of Rnase On Rasf Cartilage Invasion In Vivosupporting

confidence: 87%

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

Zimmermann-Geller

Köppert

Fischer

et al. 2016

The Journal of Immunology

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Extracellular RNA (exRNA) has been characterized as a molecular alarm signal upon cellular stress or tissue injury and to exert biological functions as a proinflammatory, prothrombotic, and vessel permeability–regulating factor. In this study, we investigated the contribution of exRNA and its antagonist RNase1 in a chronic inflammatory joint disease, rheumatoid arthritis (RA). Upon immunohistochemical inspection of RA, osteoarthritis (OA), and psoriatic arthritis synovium, exRNA was detectable only in the RA synovial lining layer, whereas extracellular DNA was detectable in various areas of synovial tissue. In vitro, exRNA (150–5000 nt) was released by RA synovial fibroblasts (RASF) under hypoxic conditions but not under normoxia or TNF-α treatment. RNase activity was increased in synovial fluid from RA and OA patients compared with psoriatic arthritis patients, whereas RNase activity of RASF and OASF cultures was not altered by hypoxia. Reduction of exRNA by RNase1 treatment decreased adhesion of RASF to cartilage, but it had no influence on their cell proliferation or adhesion to endothelial cells. In vivo, treatment with RNase1 reduced RASF invasion into coimplanted cartilage in the SCID mouse model of RA. We also analyzed the expression of neuropilins in synovial tissue and SF, as they may interact with vascular endothelial growth factor signaling and exRNA. The data support the concepts that the exRNA/RNase1 system participates in RA pathophysiology and that RASF are influenced by exRNA in a prodestructive manner.

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Section: Effect Of Rnase On Rasf Cartilage Invasion In Vivosupporting

confidence: 87%

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

Zimmermann-Geller

Köppert

Fischer

et al. 2016

The Journal of Immunology

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“…Given the multiplicity of cytokines, growth factors, matrix degradation products, and lipid mediators found within the proinflammatory environment that characterizes RA (1-4), it will likely prove difficult to identify a dominant MT1-MMP regulator (50). Indeed less "classical" inflammatory mediators such as hypoxia, HIF-2b, Wnt family members, or epigenetic changes in DNA methylation may well serve as dominant players in the control of MT1-MMP expression or activity in RA (64)(65)(66)(67)(68)(69). Nevertheless, given the expression of MT1-MMP within RA synoviocytes at sites of tissue damage in vivo, its pathophysiologically relevant functional properties, and the recent development of MT1-MMP-specific inhibitors (70), the proteinase could serve as an important target for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

Sabeh¹,

Fox

Weiss³

2010

The Journal of Immunology

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“…Hypoxia is prevalent in multiple inflammatory scenarios, such as inflammatory bowel diseases (IBDs) and rheumatoid arthritis (RA) (5)(6)(7)(8). The intestinal mucosa exhibits an O 2 gradient from crypt to villus, wherein O 2 is highest in the crypts and lowest in the villus tips, which are closest to the anoxic gut lumen (9).…”

Section: Inflammation and Hypoxiamentioning

confidence: 99%