Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

Abstract

Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done in vivo using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration.

Nanoparticle-based inhibition of vascular endothelial growth factor receptors alleviates osteoarthritis pain and cartilage damage

“…2A) permits initial drug loading of up to half-maximal efficiency (~50%) with near-maximal drug encapsulation efficiency A single iA injection of nano-PAZii (top right) suffices for the rapid and sustained reduction of knee joint pain. the therapeutic effects of nano-PAZii are attributable to inhibition of veGFR1/Flt1, which relieves chronic OA pain, and inhibition of veGFR2/FlK1, which protects cartilage from OA-related degradation (bottom right), consistent with our previous studies (15). At the cellular level, pazopanib released by nano-PAZii in cartilage and synovium (bottom left) reduces negative biomarkers (e.g., inflammatory, neural, and cartilage catabolic factors) and increases positive biomarkers (e.g., cartilage extracellular matrix proteins).…”

“…Several VEGF ligands (e.g., VEGFA, VEGFB, and VEGFC) might play a part during OA progression and pain (10,11). Direct evidence for the role of VEGFs suggests that intraarticular (IA) injection of VEGFs into the knee joint mimics OA-like joint pathology and inhibition of VEGF signaling retards OA progression (12)(13)(14)(15)(16). These ligands converge on two cognate cell surface receptors (e.g., VEGFR1/FLT1 and VEGFR2/FLK1) that have mechanistically distinct pathological roles: VEGFR1 is primarily responsible for joint pain transmission, while VEGFR2 is linked to cartilage degeneration (15).…”

“…Direct evidence for the role of VEGFs suggests that intraarticular (IA) injection of VEGFs into the knee joint mimics OA-like joint pathology and inhibition of VEGF signaling retards OA progression (12)(13)(14)(15)(16). These ligands converge on two cognate cell surface receptors (e.g., VEGFR1/FLT1 and VEGFR2/FLK1) that have mechanistically distinct pathological roles: VEGFR1 is primarily responsible for joint pain transmission, while VEGFR2 is linked to cartilage degeneration (15). Therefore, the simultaneous inhibition of both receptors represents a very attractive two-pronged strategy for OA treatment.…”

“…The biological half-life of pazopanib is 31.9 hours, and daily dosing has been recommended clinically (20,21). Reduction of OA pain by IA injection of pazopanib lasts only for 1 to 2 days in our preclinical animal model (15). Hence, reduction in the dosing frequency of pazopanib requires consideration of delivery methods that prolong the bioavailability of pazopanib.…”

“…First, pinpointing the optimal OA stage for VEGFR1 and VEGFR2 (e.g., post-injury, early OA, and advanced stages) dual inhibition is vital. Second, our prior research indicated that VEGFR inhibitors (e.g., pazopanib) require consistent drug injections (twice per week) for knee OA therapy ( 15 ). The frequency is clinically undesirable due to increased infection risk and other adverse effects (e.g., soft tissue damage), as well as the requirement for repetitive hospital visits and patient compliance ( 18 , 19 ).…”