Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by bone erosion and cartilage destruction in the joints. Many of the conventional antiarthritic drugs are effective in suppressing inflammation, but they do not offer protection against bone damage. Furthermore, the prolonged use of these drugs is associated with severe adverse reactions. Thus, new therapeutic agents that can control both inflammation and bone damage but with minimal side effects are sought. Celastrus is a Chinese herb that has been used for centuries in folk medicine for the treatment of various inflammatory diseases. However, its utility for protection against inflammation-induced bone damage in arthritis and the mechanisms involved therein have not been examined. We tested celastrus and its bioactive component celastrol for this attribute in the adjuvant-induced arthritis model of RA. The treatment of arthritic rats with celastrus/celastrol suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints as demonstrated by histology and bone histomorphometry. The protective effects against bone damage are mediated primarily via the inhibition of defined mediators of osteoclastic bone remodeling (e.g. receptor activator of nuclear factor-κB ligand (RANKL)), the deviation of RANKL/osteoprotegerin ratio in favor of antiosteoclastic activity, and the reduction in osteoclast numbers. Furthermore, both the upstream inducers (proinflammatory cytokines) and the downstream effectors (MMP-9) of the osteoclastogenic mediators were altered. Thus, celastrus and celastrol controlled inflammation-induced bone damage by modulating the osteoimmune cross-talk. These natural products deserve further consideration and evaluation as adjuncts to conventional therapy for RA.