What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

• Published in: Clinical orthopaedics and related research 2023-08, Vol.481 (8), p.1634-1647
• Main Authors: Mert, Lezgin, Bilgiç, Bilge, Şenol, Başak Koç, Zülfikar, Osman Bülent, Durmaz, Hayati, Polat, Gökhan
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Arthritis; Basic Research; Bevacizumab; Bevacizumab - metabolism; Bevacizumab - pharmacology; Cartilage; Cartilage (articular); Cartilage diseases; Cartilage, Articular - diagnostic imaging; Hemarthrosis - drug therapy; Hemarthrosis - etiology; Hemarthrosis - metabolism; Hemophilia; Humans; Injection; Injections, Intra-Articular; Knee; Magnetic resonance imaging; Male; Membrane permeability; Osteoarthritis; Rabbits; Synovial Membrane - diagnostic imaging; Synovium; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Western blotting
• ISSN: 0009-921X; 1528-1132; 1528-1132
• DOI: 10.1097/CORR.0000000000002628

Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits' ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Intra-articular bevacizumab treatment inhibited VEGF in our ra