RRC ID 72637
Author Franco-Trepat E, Guillán-Fresco M, Alonso-Pérez A, López-Fagúndez M, Pazos-Pérez A, Crespo-Golmar A, Gualillo O, Jorge-Mora A, Bravo SB, Gómez R.
Title Repurposing drugs to inhibit innate immune responses associated with TLR4, IL1, and NLRP3 signaling in joint cells.
Journal Biomed Pharmacother
Abstract Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses.
Volume 155
Pages 113671
Published 2022-9-12
DOI 10.1016/j.biopha.2022.113671
PII S0753-3322(22)01060-5
PMID 36108390
IF 4.545
Human and Animal Cells ATDC5(RCB0565)