Tetrandrine inhibits the occurrence and development of frozen shoulder by inhibiting inflammation, angiogenesis, and fibrosis

Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects. To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats. A controlled laboratory study. Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements. No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P < 0.01). Immunohistochemical staining showed no abnormal angiogenesis or fibrosis in the TET group or the control group. However, significant angiogenesis, collagen remodeling, and fibrosis were observed in the FS group, and the expression and proportion of type I and type III collagen in the FS group were significantly higher than those in the TET group or the control group (P < 0.01). TEM observation showed that TET protected the ultrastructure of collagen fibrous reticular arrangement of the articular capsule and prevented the formation of scar-like fibrotic structures, which are unique to FS. The significantly increased expression of Smad7 and the suppressed expression of Smad 2 in the TET group compared with that of the FS group indicated that TET also significantly inhibited the TGF-β1 intracellular signal pathway. The expression of profibrogenic factors and proinflammatory cytokines in the TET group and the control group was significantly lower than that in the TET group (P < 0.01). The results demonstrated that TET protected the normal reticular structure of the capsule during the freezing period and prevented the development of FS by inhibiting inflammation, angiogenesis, and fibrosis in a rat FS model. TET may be a safe and effective clinical medication for preventing and treating FS.