Toddalolactone Protects Against Osteoarthritis by Ameliorating Chondrocyte Inflammation and Suppressing Osteoclastogenesis

Background: Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn’t been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo . Methods: : LPS (10μg/ml) was employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs); Meanwhile, the effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results: : We found that TOD inhibited the expression of inflammatory and catabolic mediators ( IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in LPS-treated chondrocytes in vitro . Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of marker genes (NFATc1 and c-fos). Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis by inhibiting the activation of the NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated the ACLT-induced cartilage erosion and inhibited bone resorption. Conclusions: : These results showed that TOD can be adopted as a potential therapeutic agent for OA.