In healthy, vascularized tissue, blood vessels are lined by endothelial cells that remain quiescent as the vessels mature with an intact pericyte layer. This state is characterized by stability of the vessels, efficient perfusion and oxygen diffusion, and minimal leukocyte migration. 

“During inflammation, however, activated endothelial cells can lose their polarity, detach, and protrude into the vessel lumen, thereby disruptinsug the pericyte layer,” wrote the authors of a new review published in Nature Reviews Rheumatology.1 The vessel becomes disorganized and dysfunctional, and the resulting increase in stromal edema and restriction of nutrient and oxygen delivery causes hypoxia.

Hypoxia has been implicated in the pathogenesis of rheumatoid arthritis (RA), as hypoxic conditions in the synovium enhances ability of inflammatory cells to accelerate proliferation and migration. In vivo studies show that levels of synovial oxygen are negatively associated with not only macroscopic synovitis, but also disease activity markers


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In inflamed joints, activated endothelial vessels allow leukocyte infiltration of the synovium and a subsequent increase in metabolic turnover of the expanding pannus. This turnover occurs more rapidly than the dysfunctional oxygen supply can accommodate, leading to increased hypoxia and metabolic demand. In addition, the oxygen diffusion distance increases, and elevated intraarticular pressure and inflammation-induced joint swelling may further compromise vascular supply and exacerbate hypoxia.

The complementary actions of vascular endothelial growth factor (VEGF) and members of the angiopoietin (Ang) family are critical for the maintenance of vessel stability and regression during the formation of RA vasculature. For example, a significant increase in the expression of Ang1, Ang2, and their receptor Tie2 has been observed in animal models during disease progression, and blocking this receptor ameliorates bone destruction. 

“Unstable vessels in the inflamed joint are associated with the presence of incomplete interactions between endothelial cells and pericytes, hypoxia and increased oxidative damage,” which may mediate endothelial cell activation, promoting angiogenesis and cartilage damage. 

Hypoxia-induced alterations in mitochondria result in decreased respiration of the mitochria, increased reactive oxygen species (ROS) production, oxidative damage, adenosine triphosphate reduction, and mitochondrial (mt)DNA mutations.

The altered mitochondria release damage associated molecular pattern (DAMP) molecules that promote immune responses. The recent finding that mitochondria are DAMP-releasing organelles indicates that they may have a central role in modulating inflammation, though the underlying mechanisms are still unclear. 

Immune-inflammatory cells show adaptive survival reactions to hypoxia by activating key proinflammatory signaling pathways, including those mediated by hypoxia-inducible factor-1α (HIF-1α), nuclear factor κB (NF-κB), and Janus kinase–signal transducer activator of transcription (JAK–STAT).  Activation of these factors may lead to additional invasion of the joint synovium. 

Potential Novel Therapeutic Approaches in RA? 

Because the reprogramming of hypoxia-mediated pathways in synovial cells has been implicated in the development of RA and other inflammatory diseases, future studies should use gene-expression profiling techniques to characterize these immune cells at the site of inflammation.  This could potentially lead to the ability to target destructive cells while leaving the overall immune repertoire intact.  

The use of glycolytic inhibitors may also be a worthwhile research focus, as it is well-established that high levels of glycolysis have been found in association with the proinflammatory functions of immune cells.  

“Reverting the metabolic profile back to oxidative phosphorylation might limit the inflammatory potential of these cells and provide a novel therapeutic approach for RA,” the authors postulated.

Summary & Clinical Applicability

Inflammation-induced hypoxia triggers the activation of endothelial cells and fibroblast-like synoviocytes, leading to impaired mitochondrial function and oxidative damage. The resulting metabolic disturbance further  exacerbates the inflammatory response.

“Targeting synovial metabolic pathways through inhibition of hypoxia-induced signaling pathways might have therapeutic benefit for rheumatoid arthritis and other inflammatory diseases,” the authors concluded.

Reference

1. Fearon U, Canavan M, Biniecka M, Veale DJ. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol. 2016; 12(7):385-97. 

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