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‐Ca2+ 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. FASEB J. 32, 3398–3410 (2018). www.fasebj.org