Tetrandrine attenuates the bone erosion in collagen‐induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase

Abstract

Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro, tetrandrine inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes. In bone marrow-derived macrophages and RAW264.7 cells, tetrandrine inhibited RANKL-induced translocation of NF-κB-p65 and nuclear factor of activated T cell 1 (NFATc1) through suppressing spleen tyrosine kinase (Syk)-Bruton's tyrosine kinase-PLCγ2-Ca signaling. Of interest, tetrandrine did not affect the phosphorylation of immunoreceptor tyrosine-based activation motifs, the conventional upstream of Syk, but it inhibited the activity of Syk by enhancing its ubiquitination and degradation. The anti-osteoclastogenesis effect of tetrandrine nearly disappeared when it was used in combination with the Syk inhibitor piceatannol or in constitutively activated Syk-overexpressing cells. Taken together, tetrandrine attenuated CIA-induced bone destruction by inhibiting osteoclastogenesis through hindering the translocation of NF-κB-p65 and NFATc1 via reducing the activation of Syk.-Jia, Y., Miao, Y., Yue, M., Shu, M., Wei, Z., Dai, Y. Tetrandrine attenuates the bone erosion in collagen-induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase.

Fangchinoline protects against bone loss in OVX mice via inhibiting osteoclast formation, bone resorption and RANKL-induced signaling

“…In addition, bone histomorphometry results revealed that the protective effects of fanchinoline is through inhibiting the osteoclasts activity by the relative parameter such as osteoclast number/ bone surface (N.Oc/BS) and osteoclast surface/ bone surface (Oc.S/BS). Our results are in line with recent findings showing an inhibitory effect of tetrandrine on bone loss (8,33), and also provide new mechanistic insights of fangchinoline. In conclusion, fangchinoline attenuated osteoclast formation, function and ameliorated OVX-induced osteoporosis in mice mainly through suppressing RANKL signalling pathways and osteoclast marker genes expression.…”

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

“…These two recent works suggest that CEP might be useful to prevent osteoporosis. Tetrandrine was also shown to attenuate bone erosion in a model of collagen-induced arthritis (Jia et al, 2018).…”

Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR-c-src-c-Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis

“…Accumulative evidence obtained from clinical and animal trials indicates that tetrandrine is relatively safer, and has been used to treat rheumatalgia and arthralgia in China for decades 9 . Our previous studies showed that tetrandrine could inhibit RANKL-induced osteoclastogenesis via enhancing the ubiquitylation and degradation of Syk, and attenuate the bone destruction in collagen-induced arthritis (CIA) rats 10 . Furthermore, tetrandrine was found to be a potential ligand of AhR, which could activate AhR and increase the expression of the downstream target gene CYP1A1 in murine T cells 9 .…”