Abstract
Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1β /IL-1R1/IL-1RAcP protein complex and its downstream signaling has been implicated in osteoarthritis pathology. Current OA therapeutic approaches target either the cytokine IL-1β or the primary receptor IL-1RI but do not exploit the potential of the secondary receptor IL-1RAcP. Our previous work implicated the Arg286 residue of IL-1RAcP as a key mediator of complex formation. Molecular modeling confirmed Arg286 as a high-energy mediator of the ternary IL-1β complex architecture and interaction network. Anti-IL-1RAcP monoclonal antibodies (mAb) targeting the Arg286 residue were created and were shown to effectively reduce the influx of inflammatory cells to damaged joints in a mouse model of osteoarthritis. Inhibitory peptides based on the native sequence of IL-1RAcP were prepared and examined for efficacy at disrupting the complex formation. The most potent peptide inhibitor had an IC50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1β signaling in a cell model by 90% at 2 μM. Overall, therapies that target the Arg286 region surface of IL-1RAcP, and disrupt subsequent interactions with subunits, have the potential to serve as next generation treatments for osteoarthritis.
Highlights
Osteoarthritis (OA), the most common form of arthritis, is a severely debilitating disease causing suffering for more than 300 million people worldwide (Brown et al, 2006; Kloppenburg and Berenbaum, 2020)
In order to identify hot spots for interface targeting via modeling and to determine interactions critical to binding and activity, a computational study of the ternary interleukin 1β (IL-1β) complex interaction was performed through classical molecular dynamics (MD) simulations and quantum mechanical calculations
Root-mean-square deviation (RMSD) (Supplementary Figure 1), RMSD clustering (Supplementary Figure 4), and fingerprinting (Supplementary Tables 1–13) established that there were minimal fluctuations in interface interactions and no major changes in secondary structure, providing a representative structure to use for further analysis and as an initial probe at studying the dynamic nature of the IL-1β–IL-1R1—IL-1RAcP complex
Summary
Osteoarthritis (OA), the most common form of arthritis, is a severely debilitating disease causing suffering for more than 300 million people worldwide (Brown et al, 2006; Kloppenburg and Berenbaum, 2020). OA is characterized by degenerative changes in articular cartilage, bone, and associated joint tissues. Post-traumatic arthritis (PTA), one of the etiologic subtypes of osteoarthritis, is a leading cause of joint disability and it is thought to IL-1RAcP Arg286 as Anti-osteoarthritis Target represent 12% of all OA cases (Punzi et al, 2016). PTA can follow a wide variety of joint or joint-associated tissue injuries including ligament and meniscal tears and articular impact (Roos et al, 1998; Lohmander et al, 2007; Chu et al, 2010). Articular fractures commonly cause accelerated joint degeneration (Furman et al, 2006). Surgical reduction and fixation of the joint does not prevent the development of PTA. There is an urgent need to develop novel therapeutic approaches for PTA after joint injury
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