Bevacizumab tested for treatment of knee osteoarthritis via inhibition of synovial vascular hyperplasia in rabbits

Background/objective: Osteoarthritis (OA) is the most common joint disorder. Angiogenesis and synovial hyperplasia are important factors in the development of OA. Previous studies demonstrated that bevacizumab, an antibody against vascular endothelial growth factor in angiogenesis for cancer treatment, might be a potential candidate for the treatment of OA. However, experimental studies were lacking in whether bevacizumab would be able to attenuate the severity of OA. In this study, we used normal New Zealand rabbits and a rabbit knee immobilization model of OA, to investigate the toxicity and efficacy of bevacizumab. Methods: In the safety test of bevacizumab, sixteen rabbits were randomly divided into 2 groups: control group and bevacizumab group (n = 8 per group). We evaluated the blood chemistry and histology of normal rabbit joints after bevacizumab treatment. In the efficacy test of bevacizumab, thirty-two rabbits were used for establishing OA model and then randomly divided into 4 groups: bevacizumab group, sodium hyaluronate (SH) group, triamcinolone acetonide (TA) group and control group (n = 8 per group). We used histological evaluations and immunohistochemistry to examine the responses to bevacizumab treatment in a rabbit model of knee immobilization-induced OA. Results: Bevacizumab treatment did not show any adverse effects histologically on normal joints. Blood tests and Mankin's score of cartilage revealed no significant difference between the bevacizumab and control groups (p > 0.05). The bevacizumab, SH, and TA groups attenuated articular cartilage degeneration and showed less synovial hyperplasia compared to the control group macroscopically and histologically, while the effect of the bevacizumab group was most obvious (p < 0.05). Immunohistochemistry revealed significantly lower vascular endothelial growth factor (VEGF) expression in the synovium and matrix metalloproteinase-1 (MMP-1) in the cartilage in the bevacizumab, SH, and TA groups compared to the control group (p < 0.05), while the expression of VEGF and MMP-1 in the bevacizumab group was the lowest among the four groups (p < 0.05). Conclusions: Intra-articular injection of 4-mg bevacizumab in rabbit knees did not show adverse effects. The bevacizumab treatment prevented joint inflammation in terms of inhibition of reduced angiogenesis, inhibited synovial proliferation, and reduced VEGF and MMP-1 expression. Compared with SH and TA, bevacizumab protected the cartilage and produced a better therapeutic effect on primary knee OA in rabbits, which imply that bevacizumab, an anticancer drug, may become a potentially effective drug for the treatment of OA. The translational potential of this article: Our study confirmed the therapeutic effect of bevacizumab on rabbit primary knee OA. This study demonstrated that bevacizumab may have clinical implications and contribute to the development of new OA treatments. (C) 2019 The Authors. Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society.