AUTHOR=Orecchini Elena , Mondanelli Giada , Orabona Ciriana , Volpi Claudia , Adorisio Sabrina , Calvitti Mario , Thuy Trinh Thi , Delfino Domenico V. , Belladonna Maria Laura 

TITLE=Artocarpus tonkinensis Extract Inhibits LPS-Triggered Inflammation Markers and Suppresses RANKL-Induced Osteoclastogenesis in RAW264.7

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.593829

DOI=10.3389/fphar.2020.593829

ISSN=1663-9812

ABSTRACT=<p><italic>Artocarpus tonkinensis</italic> (<italic>At</italic>) leaf decoction, a traditional remedy prepared in North <italic>Vietnam</italic> by the Hmong ethnic group, is a tea extract rich in bioactive compounds that may have therapeutic effects in arthritis and backache. Indeed, it has been demonstrated that <italic>At</italic> is able to inhibit Th17 lymphocytes development and to protect mice in an experimental model of collagen-induced arthritis. By resorting to macrophage <italic>in vitro</italic> models of inflammation and osteoclastogenesis, we showed that <italic>At</italic> extract significantly reduced nitric oxide synthase 2 (NOS2) activity and IL-6 production by RAW 264.7 murine cells. Moreover, <italic>At</italic> demonstrated an anti-osteoclastogenic effect, as revealed by complete inhibition of TRAP-positive osteoclast formation and decreased expression of key osteoclast-related genes. This <italic>At</italic> activity likely relies on the inhibition of RANK downstream signaling pathway, as the activation of non-receptor tyrosine kinase Src is reduced upon RANKL-<italic>At</italic> exposure. Protective effect of <italic>At</italic> against bone loss was also enlightened <italic>in vivo</italic> by collagen-induced arthritis (CIA) experiment demonstrating that, although paw edema was only weakly opposed by drinking <italic>At</italic> decoction, bone and cartilage were well preserved in CIA+<italic>At</italic> mice and joint tissue expressed decreased levels of osteoclast marker genes respect to CIA control group. Maesopsin 4-O-β-D-glucoside (i.e., TAT-2, one of the main decoction bioactive components) was capable to contrast NOS2 activity, IL-6 expression and osteoclast formation, too, albeit to a lesser extent when compared to <italic>At</italic> decoction. Overall, this study enlightens another <italic>At</italic> cell target, macrophages, beside Th17 lymphocytes, and suggests that the anti-arthritic beneficial effects of <italic>At</italic> decoction largely derives from its ability to counteract not only inflammation, but also osteoclastogenesis.</p>