Inhibition of the MALT1-LPCAT3 axis protects cartilage degeneration and osteoarthritis

• DOI: 10.1186/s12964-024-01547-4
• Publication Date: 2024-03-22T17:02:33Z
• Authors: Vijay Kondreddy; Rajkumar Banerjee; B. L. A. Prabhava...; Kathirvel Muralid...; Selvakumar Pirama...
• Keywords: Cartilage, Articular; Alternative medicine; Osteoarthritis and Cartilage Repair; Interleukin-1beta; Cyclooxygenase-2 Inhibitors in Inflammation and Cancer; Biochemistry; Gene; Mice; Pathology; RNA, Small Interfering; Cells, Cultured; Immunology and Microbiology; 0303 health sciences; R; 1-Acylglycerophosphocholine O-Acyltransferase; Life Sciences; Gene silencing; Proinflammatory cytokine; Small interfering RNA; Downregulation and upregulation; Chemistry; Cytokines; Medicine; Matrix Metalloproteinase 3; Anatomy; Cell biology; LPCAT3; Immunology; Cancer research; Transfection; 03 medical and health sciences; Chondrocytes; Innate Immune Recognition and Signaling Pathways; Rheumatology; Health Sciences; Osteoarthritis; Animals; Humans; Biology; Pharmacology; Inflammation; QH573-671; MALT1; Research; FOS: Clinical medicine; Endothelial Cells; Cartilage; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Lipid nanoparticles; Eicosanoids; MMP3; Gene expression; Cytology

AbstractThe proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1β-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1β-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1β-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines. Graphical Abstract