Exploration of therapeutic effects on the hypoxic pathway in inflammatory arthritis

Thesis

Synovial hypoxia is a feature of inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Whether joint hypoxia is a consequence or a cause of inflammatory arthritis is poorly understood. Targeting hypoxia in the inflamed joint directly would provide insight as to whether hypoxia is driving synovial inflammation. Lecithin encapsulated oxygen nanobubbles were purported to act as oxygen carriers that may relieve peripheral tissue hypoxia.

These nanobubbles were assumed to carry oxygen given that they downregulated hypoxia-inducible factor (HIF) 1α. I demonstrated that nanobubbles downregulated HIF-1α protein expression and hypoxia response element (HRE) transcription in vitro irrespective of gas loading. Animal and human in vivo studies by others confirmed that oxygen nanobubbles did not increase tissue oxygenation. Nanobubbles therefore would not be expected to relieve joint hypoxia and my proposed clinical study of nanobubbles was withdrawn.

Synovial hypoxia has been shown to be relieved in patients with inflammatory arthritis who responded to anti-inflammatory biologic therapies. Intra-articular methylprednisolone injection is a widely used anti-inflammatory treatment for inflammatory arthritis. I found that intra-articular methylprednisolone did not affect synovial fluid oxygen levels at 4 weeks follow-up, although interleukin-6 (IL-6) and tumour necrosis factor (TNF) cytokines were reduced at least in the PsA subgroup.

Single nucleus transcriptomic analysis of synovial tissue biopsies at baseline and 4 weeks after intra-articular methylprednisolone injection showed no change in hypoxia related genes. This in vivo therapeutic atlas found that tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in lining fibroblasts and lipogenesis was upregulated in adipocytes after methylprednisolone treatment, consistent with previous studies. Exploratory analysis of lining fibroblasts showed upregulation of matrix Gla protein (MGP) in RA and bone morphogenetic protein-binding endothelial regulator (BMPER) in PsA, which may account for the preponderance of bony erosions in RA and bushy tortuous vasculature in PsA.

Authors: Law, S

• DOI: 10.5287/ora-qa4xgo5bp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English