Systematic analysis of inflammation and pain pathways in a mouse model of gout

Abstract

Gout is a prevalent and painful inflammatory arthritis, and its global burden continues to rise. Intense pain induced by gout attacks is a major complication of gout.However, systematic studies of gout inflammation and pain are lacking. Using a monosodium urate (MSU) crystal-induced gout model, we performed genome-wide transcriptome analysis of the inflamed ankle joint, dorsal root ganglion (DRG), and spinal cord of gouty mice. Our results revealed important transcriptional changes, including highly elevated inflammation and broad activation of immune pathways in both the joint and the nervous system, in gouty mice. Integrated analysis showed that there was a remarkable overlap between our RNAseq and human genome-wide association study (GWAS) of gout; for example, the risk gene, stanniocalcin-1 (STC1) showed significant upregulation in all three tissues. Interestingly, when compared to the transcriptomes of human osteoarthritis (OA) and rheumatoid arthritis (RA) joint tissues, we identified significant upregulation of cAMP/cyclic nucleotide-mediated signaling shared between gouty mice and human OA with high knee pain, which may provide excellent drug targets to relieve gout pain. Furthermore, we investigated the common and distinct transcriptomic features of gouty, inflammatory pain, and neuropathic pain mouse models in their DRG and spinal cord tissues. Moreover, we discovered distinct sets of genes with significant differential alternative splicing or differential transcript usage (DTU) in each tissue, which were largely not detected by conventional differential gene expression analysis approaches. Based on these results, our study provided a more accurate and comprehensive depiction of transcriptomic alterations related to gout inflammation and pain.

Single-cell and genome-wide Mendelian randomization identifies causative genes for gout

“…Inhibition of MAP2K11 expression or activity protects renal function and uric acid excretion by preventing hyperuricemia-induced apoptosis and autophagy in renal tubular epithelial cells [ 43 ]. Inhibiting the expression or activity of MAP2K11 in a mouse model study decreased the severity of gouty arthritis by inhibiting the apoptosis and autophagy of synoviocytes and chondrocytes [ 44 ]. Involved in the beginning and development of arthritis with gout, MAP2K11 is highlighted as a potential therapeutic target by these findings.…”

Hyperuricemia remodels the serum proteome toward a higher inflammatory state

“…VEGFA has been previously associated with serum urate concentrations in a human genome-wide association study 71 as well as in a mouse model of gout. 72 VEGFA is a pro-angiogenic factor produced by synovial monocytes and fibroblasts upon stimulation by IL-1β, TGF-β, and other mediators 73 and which can also act as a chemoattractant for monocytes and neutrophils. 74 VEGFA can induce MMP-1 and other MMPs which promote angiogenesis by degrading the extracellular matrix and allowing for the migration of new cells within the synovium and proliferation of new blood vessels.…”

Store‐operated calcium entry mediates hyperalgesic responses during neuropathy

“…Molecular alterations are recognized as the basis for behavioral phenotypes and neural plasticity, likely contributing to nocifensive sensitization associated with neuropathic pain [ 51 ]. Proinflammatory factors such as NALP3 inflammasome, IL‐1β, and IL‐18, are shown to exhibit direct neural excitotoxicity that results in the accumulation of glutamate in the synaptic cleft and increases excitability at the early stage of pain [ 52 ]. Bath application of proinflammatory factors immediately enhances the frequency of spontaneous EPSCs (sEPSCs), which may further trigger long‐term synaptic plasticity by inducing inflammation [ 53 ].…”