Where are we in targeting hypoxia-induced pathways in inflammatory arthritis? Current understanding, insights, and future directions

Introduction: Joint tissues affected by inflammatory arthritis (IA) create hypoxic microenvironments that sustain the inflammatory response. Although targeting molecules in hypoxia-induced pathways has provided valuable insights into potential novel therapies for various types of IA, progress remains preclinical, and no clinical trials have been conducted for IA. Methods: A literature search was conducted to create a narrative review exploring the role of hypoxia and its signaling pathways in IA pathogenesis, as well as the potential and future directions for IA therapies that target hypoxia-induced molecules before moving forward to clinical applications. Results: Hypoxia is a prevalent feature of the IA synovial microenvironment and contributes to disease progression. Various studies and preclinical models demonstrate how hypoxia-inducible factors, vascular endothelial growth factors, and matrix metalloproteinases, among other molecules, influence rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Despite these findings, drug development targeting these molecules in IA has been limited due to challenges in delineating the mechanistic pathways of hypoxia, the distinct roles of hypoxia-induced molecules depending on anatomical sites, and concerns regarding pharmacokinetics and patient safety. However, given that hypoxia-induced molecule-targeting therapies have been successfully approved for treating cancers and cardiovascular diseases, further research is needed to advance the application of similar medications in IA. Conclusions: Given the pathogenic effects of hypoxic microenvironments in IA, it is imperative to continue gathering compelling evidence to advance hypoxia-induced therapies. Furthermore, elucidating the safety and efficacy of such drugs in various preclinical models, in collaboration with chemists and the pharmaceutical industry, is crucial for accelerating the development of novel, optimized treatment methods.