Inhibitory effect of lenvatinib, a multiple receptor tyrosine kinase inhibitor, on osteoarthritis

Abstract

Purpose: With the initial damage to articular cartilage due to aging or trauma as its origin, osteoarthritis (OA) progresses towards a disease state causing cartilage degeneration, synovitis, and osteophyte formation. The angiogenic factor vascular endothelial growth factor (VEGF) is involved in synovitis and angiogenesis in cartilage tissue, and in recent studies, anti-VEGF therapies have been reported to suppress synovitis and OA. In this study, we investigated the effects of Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, on synovitis and osteophyte formation in a rabbit model. Methods: Anterior cruciate ligament transection (ACLT) was performed on one knee of each rabbit to induce traumatic OA and to allow the evaluation of pain behavior in terms of weight-bearing asymmetry. Lenvatinib was administered orally from 5 weeks to 8 weeks after ACLT. We classified the rabbits into 4 groups according to the following Lenvatinib dosages: group A=no administration (n=12); group B=0.3 mg/kg/day (n=15); group C=1.0 mg/kg/day (n=14); and group D=3.0 mg/kg/day (n=13). We measured the weight distribution ratio of the damaged versus undamaged limbs using the Linton incapacitance tester (Linton Instrumentation) for pain evaluation at 4, 6, 8, 10, and 12 weeks after ACLT. Rabbits were sacrificed at 12 weeks after ACLT. The femoral condyles were examined macroscopically. We checked and evaluated osteophyte formation using an osteophyte formation score developed by Tibesku. Histological sections of the synovium were stained for hematoxylin and eosin and evaluated using a synovitis score developed by Kreen. In addition, adverse events including body weight gain rate before and after administration of Lenvatinib were evaluated. Results: The weight distribution ratio at 12 weeks postoperatively was 38.9 ± 5.2% in group A, 47.3 ± 3.4% in group B, 47.4±3.0% in group C, and 42.8±5.2% in group D, and significant differences were observed between A and B (P <0.01) and between A and C (P <0.01). Osteophyte formation score was 2.1±0.5 in group A, 1.2±1.1 in group B, 1.2±0.7 in group C, and 1.0±0.6 in group D, and significant differences were observed between A and B (P <0.05), A and C (P <0.05), and A and D (P<0.01). The synovitis score was 4.3±1.4 in group A, 2.6±0.9 in group B, 2.7±1.0 in group C, and 2.7±1.1 in group D, and significant differences were observed between A and B (P <0.05), A and C (P <0.05), and A and D (P<0.05). There was no significant difference in body weight gain rate between the non-administered group and the administered groups, and no adverse events were detected. Conclusions: In this study, our results suggest that oral administration of Lenvatinib may inhibit synovitis and reduce pain in a rabbit ACLT model. We previously reported that both intravenous and intra-articular administrations of bevacizumab, an anti-VEGF antibody, inhibit OA in a similar model. Lenvatinib is a safe orally administrable VEGF inhibitor which is easier to administer than other VEGF inhibitors and has the potential to be applied clinically. It may also be a more effective angiogenesis inhibitor because of its higher selectivity towards VEGFR and FGFR than other angiogenesis inhibitors, as existing VEGF inhibitors are known to enhance FGF-2 production by the inhibition of VEGF and consequently enhance VEGFR signaling.View Large Image Figure ViewerDownload Hi-res image Download (PPT)