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

摘要: Recently, we reported that tetrandrine, a natural alkaloid, could inhibit the osteoclastogenesis and bone erosion through enhancing ubiquitination degradation of spleen tyrosine kinase (Syk). Herein, addressed whether how aryl hydrocarbon receptor (AhR) mediate effect tetrandrine. In vitro, tetrandrine was shown to repress RANKL-induced expression osteoclast-related marker genes, which almost completely reversed by either AhR antagonist CH223191 or siRNA. pre-osteoclasts, enhanced Syk AhR/c-src/c-Cbl signaling pathway, downregulated phospho-Syk phospho-PLCγ2, inhibited nuclear translocation NFATc1, master transcription factor for osteoclastogenesis. Notably, acted non-genomic pathway ligand-activated AhR, as evidenced fact did not change in absence translocator. collagen-induced arthritis rats, oral administration decreased number phospho-Syk-positive cells osteoclasts, reduced areas proximal tibial epiphysis excluding cortical bone. A combined use with abolished These findings revealed consequently repressed destruction AhR-c-src-c-Cbl pathway.