Joint replacement is a common surgical procedure for the terminal stages of degenerative joint diseases including rheumatoid arthritis and osteoarthritis. 1 Despite advances in surgical procedures and prosthetic material, peri-prosthetic osteolysis and the resulting aseptic loosening remains a major complication leading to implant failure. 2 Titanium (Ti)-based biomaterials are by far the most commonly used prosthetic implants due to their superiority in load-bearing applications and excellent mechanical strength and resilience. 3 However, it has now been suggested that wear particles derived from the metal biomaterial provoke an inflammatory response that subsequently induces osteoclast-mediated bone destruction around the bone-implant interface. 4 The underlying molecular mechanism that bridges the initial inflammatory response to subsequent bone destruction is complex but involves the production and release of chemokines and cytokines that predominantly promote osteoclast recruitment and activity causing localized bone loss. 5

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Objectives Limonin has received significant attention due to its multiple biological effects, intervertebral disc degeneration (IDD) is also of interest due to the high prevalence of this disease. In this study, we determined the effects of limonin on IDD and the underlying mechanism of action to find novel ways to treat IDD. Methods An IL-1β-induced cell inflammation model and a lumbar instability model inducing IDD were established to assess the progression of IDD with or without limonin treatment. We further evaluated MAPK/NF-κB and necroptosis pathways and alterations in the extracellular matrix specific within the disc. Key findings Limonin suppresses inflammation in the nucleus pulposus in vitro by reducing the production of pro-inflammatory markers such as iNOS and COX-2. Limonin reduced the activation of the MAPK/NF-κB signalling pathway and the RIP1/RIP3/MLKL necroptosis pathway in the NP cells. Moreover, limonin delays the IDD progression in the lumbar instability model. Conclusions Limonin could potentially delay IDD by inhibiting NP cell necroptosis and modulating peripheral matrix proteins within the intervertebral disc and is a potential pharmacological research direction for the therapy in patients with IDD.

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