Hypoxia as an amplifier of synovial inflammation in rheumatoid arthritis.

Inflammatory arthritis is characterized by neovascularization, leukocyte extravasation and synovial hyperplasia, leading to joint destruction and functional disability. Although increased synovial angiogenesis is a hallmark of synovial inflammation, efficiency of the oxygen supply to the synovium is poor, leading to a hypoxic gradient that impacts differential cellular responses. This hypoxic gradient occurs as infiltrating cells and cells that reside within the joint increase their metabolic demand beyond what the highly dysregulated vasculature can supply. This hypoxic environment favours an increase in reactive oxygen species, leading to oxidative damage that further promotes inflammation. In this adverse microenvironment, synovial cells adapt to generate energy and switch their cellular metabolism from a resting regulatory state to a highly metabolically active state, enabling them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates that function as signalling molecules, which further dictate the inflammatory response. However, the synovium is a complex multicellular tissue, and the specific cellular reliance on oxygen and metabolites differs across the synovium. Cellular demands depend on anatomical location, cell-cell interactions and competition for nutrients. Understanding the complex interplay between hypoxia-induced signalling pathways, oxidative stress and inflammatory responses will provide a better insight into the underlying mechanisms of disease pathogenesis.