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Disease modification in Rheumatoid Arthritis using AMPK directed therapies; restoring metabolid balance to innate immune pathways

Rheumatoid Arthritis (RA) is a common disease, which is characterised by the inflammatory destruction of synovial joints leading to pain and permanent disability. RA is also associated with premature sarcopenia, insulin resistance and increased mortality from age-associated illnesses including cardiovascular disease and malignancy. Increasing evidence that altered glucose handling contributes to pro-inflammatory sequelae, coupled with evidence that hypoglycaemic therapies exert anti-inflammatory effects, suggest bi-directionality between the control mechanisms of glucose homeostasis and inflammation.
AMP-activated protein kinase (AMPK) is a highly conserved protein kinase, which responds to low glucose availabilty by downregulating glycolysis, increasing mitochondrial respiration and switching off energy expensive anabolic cellular activities such including protein synthesis and cell cycle progression. In inflammation, where AMPK becomes inactivated by dephosphorylation, marked enhancement of glucose consumption through aerobic glycolysis is accompanied by the orchestrated upregulation of pro-inflammatory genes and effector responses. Treatment with known AMPK activating drugs reverses this effect in cell models, and switches off inflammation by down-regulating pro-inflammatory mediators including NFkB and HIF-1α.
In this pre-clinical study, using in-vitro and ex-vivo bioassays on primary RA tissue, and an in-vivo AMPK-knockout CAIA mouse model of RA, we will quantify the anti-inflammatory effects of the known AMPK activating compounds metformin, AICA-Riboside and A-769662 on critical events which orchestrate synovial inflammation in RA including angiogenesis, cell migration, proliferation and matrix degradation. Using an in vivo murine AMPK-knockout Collagen Antibody Induced Arthritis model of RA, we will demonstrate that the efficacy of these pharmacological agents in vivo is dependent on AMPK. Finally using a bioenergetic approach of mitochondrial function and extracellular flux analysis we will demonstrate AMPK activation acts in concert with AMPK-directed metabolic events. We will demonstrate sufficient preclinical evidence to justify the novel use of AMPK therapies in inflammation, leading directly to the testing of these drugs in humans with RA.