Iridoid Glycosides From Morinda Officinalis F. C. How Alleviate Rheumatoid Arthritis and Its Associated Bone Deterioration and Protect Against Methotrexate-induced Toxicity in Collagen-induced Arthritic Rats

Abstract Background: Morinda officinalis F.C.How (MO), also known as “Ba-Ji-Tian” in Chinese, has long been used to treat osteoporosis and rheumatoid arthritis (RA) in China, knowing that iridoid glycosides (IG) isolated from this plant possess anti-inflammatory, anti-osteoporotic and analgesic activities. The study was to evaluate the ameliorating effect of MOIG on joint swelling and bone destruction and the protective effect against MTX toxicities.Methods: The anti-arthritic activity of MOIG was investigated by clinical arthritis scoring, paw swelling inspection, as well as histological analysis in CIA rats. The anti-bone loss activity of MOIG was evaluated by bone mineral density (BMD) and bone morphometric analysis assessed by Micro-CT and biochemical parameters in serum related with bone metabolism. The serum metabolomics and NF-κB signaling pathway were used to explore and clarify the action mechanism.Results: The results showed that MOIG was able to alleviate the paw swelling and arthritic severity, and reduce the synovial tissue proliferation and inflammatory cell infiltration in the CIA rats. In addition, MOIG decreased bone loss and improved the micro-structure of the bone trabecular in CIA rats through regulating bone formation and bone resorption. MOIG could also reduce effectively protect against MTX-induced damage to the liver, lung and stomach. The result of metabolomics analysis showed that MOIG was involved in the regulation of D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis, and alanine, aspartate and glutamate metabolism. Furthermore, MOIG inhibited OC formation and differentiation through participating in LPS-induced NF-κB signaling. Conclusion: MOIG could attenuate the paw swelling and bone loss through regulation of amino acid metabolism, reduce the side effects caused by MTX, and may serve as a novel therapeutic for the management of patients with rheumatoid arthritis (RA).