Construction of gouty arthritis models with 3D bioprinted human synovium-cartilage systems for drug repurposing and evaluation

Current research on human gouty arthritis (GA) lacks in vitro models that can faithfully replicate native synovium and cartilage pathophysiology. Here, this work describes human synovium-cartilage culture systems composed of type II collagen-based scaffolds repopulated with human chondrocytes and 3D-bioprinted tri-lamellar hydrogels, wherein the top layer recapitulates the synovial sublining by incorporating human proinflammatory macrophages and human umbilical vein endothelial cells, whereas the synovial lining layer is collectively reconstituted by the middle layer laden with human synovial fibroblasts and the bottom layer harboring human protective barrier macrophages. Monosodium urate crystals (MSUs) are supplemented into the optimized 3D co-culture system to cooperatively initiate the inflammatory cascade. The system accurately reproduces GA-associated tissue damage, inflammation, and extracellular matrix degradation, and is responsive to anti-gout drugs including colchicine and quercetin. Transcriptomic profiling identifies inflammatory response and vascular development as pivotal regulators of pathological alterations underlying GA. Building on these mechanistic insights, proteomics analysis and validating experiments demonstrated that paeoniflorin (Pae), an anti-inflammatory and anti-angiogenic monoterpene glycoside, attenuates inflammation and neovascularization in the established GA model, which is associated with the suppression of COX2 and VEGFR1 expression. Furthermore, Pae is found to block the disease progression in a mouse model of MSU-induced GA. This study provides a promising human synovium-cartilage in vitro platform for preclinical anti-gout drugs screening and identifies potential therapeutic candidates for GA treatment.