Abstract:
Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation
of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown
to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro
anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of
inflammation markers were determined by ELISA, Western blotting and microarray, respectively.
RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 µM). The
productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and
MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX
families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and
p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor
attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed
that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA.
Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats.
Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage
erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and
restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together,
KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting
the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential
therapeutic agent for OA.
