Pristimerin

Invasive fibroblast-like synoviocytes (FLS), inflammatory macrophages and osteoclasts are the main three contributors to rheumatoid arthritis (RA) progression by promoting synovial inflammation and destructing cartilage and bone.Targeting these three cell types for restoring the inflammatory homeostasis microenvironment may be a promising anti-RA strategy.Herein, we prepared a reactive oxygen species (ROS)-responsive micelles (DPTM) to co-load dexamethasone (DEX) and pristimerin (PRI) for RA therapy.This ROS-responsive system exhibits the following advantages: (1) It makes use of the "ELVIS" effect for passive delivery and targeting the ROS environment of RA-related cells to rapidly release the payload drugs DEX and PRI. (2) Compared with free drugs, DPTM showed stronger effect on the inhibition of RA-FLS proliferation and the promotion of RA-FLS apoptosis.Moreover, DPTM could significantly weaken the migration ability of RA-FLS as indicated by the results of wound healing assay and transwell assay. (3) DPTM exerted stronger cellular uptake and anti-inflammatory effect in M1 macrophages. (4) In the model studying receptor activator of nuclear factor kappa-B ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMDMs) to osteoclasts, DPTM showed a stronger inhibitory activity on osteoclast formation as compared to free drugs.Taken together, these results highlighted the potential of DPTM for targeted RA therapy via inhibition of RA-FLS abnormal activation, macrophage polarization and osteoclastogenesis.

Rheumatoid arthritis (RA) is an autoimmune disease of the synovial joints. Pro-inflammatory cytokines produced by various immune cells drive the chronic inflammatory processes that lead to joint damage. Many drugs are available for the treatment of RA, but a significant proportion of patients do not respond adequately to them and/or have severe adverse effects. Accordingly, there is an urgent need for new therapeutics for RA. Therefore, we tested pristimerin, a natural triterpenoid, for its anti-arthritic activity in experimental RA.

Collagen antibody-induced arthritis (CAIA) was induced in DBA/1 mice. After the onset of arthritis, mice were injected daily intraperitoneally with pristimerin or vehicle for 9 days. The severity of clinical arthritis was graded and further validated by micro-computed tomography and histological examination of the hind paws. Defined mediators of arthritogenic processes were quantified by gene expression in the spleen and further validated by immunohistochemistry of paws.

We observed that pristimerin can effectively control arthritis progression in CAIA mice. A preliminary exploration of the mechanisms showed that pristimerin targeted key pro-inflammatory cytokines and chemokines, along with specific mediators of angiogenesis, bone remodelling, and cellular signalling, including the Notch signalling pathway.

This is the first report on pristimerin for its use in the treatment of antibody-induced arthritis and for the targeting of Notch pathway in arthritis by this triterpenoid. As pristimerin can control the effector phase of arthritis, our results are promising for the translation of this experimental therapy to RA patients.