Anemone flaccida Fr. Schmidt is used in the clinical compound prescription for the treatment of
rheumatoid arthritis (RA) in China and has the traditional use of draining dampness, diminishing swelling, and relieving
pain. Total
saponins (TS) are the characteristic components and also the main active ingredients of A. flaccida. Previous reports indicated that TS possess anti-inflammatory and immunoregulatory properties; however, the effects of TS on bone destruction of RA have not been evaluated. In this study, our data first showed the
therapeutic effects of TS on severity of
arthritis and
arthritis progression in
collagen-induced arthritis (CIA) rats. Then, by microfocal computed tomography (CT) quantification, TS significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints both at peri-articular and extra-articular locations. TS also diminished the level of the
bone resorption marker CTX-I and simultaneously increased the bone formation marker
osteocalcin in sera of CIA rats. Interestingly, TS prevented bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of nuclear factor-κF (
RANK) ligand (RANKL) and RANK, increasing the expression of
osteoprotegerin (OPG), at both
mRNA and
protein levels, and decreasing the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. This was further confirmed in the co-culture system of human fibroblast-like synovial and peripheral blood mononuclear cells. In addition, TS inhibited the levels of pro-inflammatory
cytokines implicated in
bone resorption, such as interleukin-1β (IL-1β),
tumor necrosis factor-α (TNFα),
IL-6,
IL-17, and
IL-23 in sera and joints. These findings offer convincing evidence that TS attenuate RA partially by preventing both focal bone destruction and systemic bone loss. This anti-erosive effect results in part from inhibiting osteoclastogenesis by regulating the RANKL/RANK/OPG signaling pathway. The suppression of systemic and local pro-osteoclastogenic
cytokines by TS was also highly effective.