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Updated: Jun 22, 2025
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Published on: September 29, 2023
Disease-Modifying Effects of Lenvatinib, a Multiple Receptor Tyrosine Kinase Inhibitor, on Posttraumatic
Yasuyuki Sogo1,2, Eriko Toyoda1,2, Toshihiro Nagai3
1Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan.
Abstract:
Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control (n = 12), L0.3: 0.3 mg/kg/day (n = 15), L1.0: 1.0 mg/kg/day (n = 14), and L3.0: 3.0 mg/kg/day (n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral-tibial (FT), femoral-patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn's grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA.
Insights
Lenvatinib, an oral angiogenesis inhibitor targeting VEGF receptors, reduced pain, synovitis, osteophyte formation, and cartilage degeneration in a rabbit osteoarthritis model. This oral medication shows potential for treating post-traumatic osteoarthritis.
Area of Science:
- Orthopedics
- Pharmacology
- Vascular Biology
Background:
- Angiogenesis and vascular endothelial growth factor (VEGF) play roles in osteoarthritis (OA) pathogenesis.
- Previous studies indicated bevacizumab's inhibitory effect on OA in a rabbit model.
Purpose of the Study:
- To investigate the efficacy of lenvatinib, an angiogenesis inhibitor, in a rabbit model of post-traumatic osteoarthritis.
- To evaluate lenvatinib's effects on synovitis, osteophyte formation, cartilage degeneration, and pain.
Main Methods:
- Post-traumatic osteoarthritis was induced via anterior cruciate ligament transection (ACLT) in rabbits.
- Rabbits received varying doses of lenvatinib (0.3, 1.0, 3.0 mg/kg/day) or served as controls.
- Pain, osteophyte formation, synovitis, and cartilage histology were assessed using weight distribution ratio, macroscopic evaluation, and histological grading systems.
Main Results:
- Lenvatinib treatment significantly reduced osteophyte formation and synovitis scores across all tested doses.
- Pain, as measured by the weight distribution ratio, was reduced in the L0.3 and L1.0 mg/kg/day groups.
- Histological analysis showed reduced cartilage degeneration and synovitis in lenvatinib-treated groups compared to controls.
- MMP3 and ADAMTS5 expression levels were reduced in lenvatinib-treated groups, particularly at the highest dose.
Conclusions:
- Oral lenvatinib effectively inhibited synovitis, osteophyte formation, and cartilage degeneration in a rabbit ACLT-induced OA model.
- Lenvatinib demonstrated a potential therapeutic effect in reducing pain associated with post-traumatic osteoarthritis.
- As an orally administered VEGF inhibitor, lenvatinib offers a convenient administration route and may be a promising treatment for post-traumatic OA.
