Inflammatory responses contribute to the pathogenesis of rheumatoid arthritis and to aspects of osteoarthritis (OA). We used the K/BxN mouse model of acute joint inflammation and cartilage breakdown to assess whether intra-articular (i.a.) administration of two agents in a nanoparticle construct might in part resolve joint specific inflammation. Firstly, we discovered that salmon calcitonin (sCT) could down-regulate RNA expression of the orphan nuclear receptor, NR4A2, which is a key regulator and potential biomarker for inflammation and represents a potentially valuable therapeutic target. This was surprising as sCT is marketed as only a second line anti-osteoporotic drug and the basis of its anti-inflammatory effects is poorly understood. sCT attenuated activated mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases 1, 3 and 13 in human cell lines: SW1353 chondrocytes as well as U937 and THP-1 monocytes. Hyaluronic acid, a recognised approved intra-articular agent used for OA by i.a. injection, also surprisingly reduced expression of NR4As and MMPs in activated cells. sCT and HA were then mixed and further down-regulated expression of NR4A2 compared to either agent alone at specific concentrations, hence the rationale for their formulation in electrostatic-based nanocomplexes (NP) using chitosan or protamine. In vitro release studies showed that the sCT released gradually over 5 days and the released peptide stimulated cAMP production in human T47D breast cancer cells expressing sCT receptors. NP containing sCT and HA were then injected by the i.a. route to the mouse knee during on-going inflammatory arthritis of the K/BxN serum transfer model and data was compared to a positive steroid control. Joint inflammation diameter was reduced together with NR4A2 expression, and local bone architecture was preserved by the NP on a par with dexamethasone. The data suggests that it might be possible to reduce the dose of steroid or replace steroids with nanoparticulate-based drug combinations for i.a. treatments of OA. Initial studies in a more established chronic model of inflammation, the collagen-induced mouse however, have been problematic as the model has high variability and in our hands thus far, responds to intra-peritoneal- but not i.a.-administered steroids or other treatments.
Disclosure of Interest None Declared
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