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

Ma, Kaige; Singh, Gurjit; Wang, Jun; O-Sullivan, InSug; Votta-Velis, Gina; Bruce, Benjamin; Anbazhagan, Arivarasu Natarajan; van Wijnen, Andre J.; Im, Hee-Jeong

doi:10.7150/ijbs.79125

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Int J Biol Sci 2023; 19(2):675-690. doi:10.7150/ijbs.79125 This issue Cite

Research Paper

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

Kaige Ma^1,2, Gurjit Singh¹, Jun Wang¹, InSug O-Sullivan¹, Gina Votta-Velis³, Benjamin Bruce⁴, Arivarasu Natarajan Anbazhagan⁵, Andre J. van Wijnen^1,6✉, Hee-Jeong Im^1,4✉

1. Department of Biomedical Engineering, the University of Illinois at Chicago, Chicago, IL, USA.
2. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3. Department of Anesthesiology, the University of Illinois at Chicago, Chicago, IL, USA.
4. Jesse Brown Veterans Affairs Medical Center (JBVAMC) at Chicago, IL 60612, USA.
5. Department of Medicine, the University of Illinois at Chicago, Chicago, IL, USA.
6. Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA.

Citation:

Ma K, Singh G, Wang J, O-Sullivan I, Votta-Velis G, Bruce B, Anbazhagan AN, van Wijnen AJ, Im HJ. Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain. Int J Biol Sci 2023; 19(2):675-690. doi:10.7150/ijbs.79125. https://www.ijbs.com/v19p0675.htm

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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.

Keywords: Osteoarthritis, cartilage degeneration, joint pain, VEGFRs, pazopanib

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APA

Ma, K., Singh, G., Wang, J., O-Sullivan, I., Votta-Velis, G., Bruce, B., Anbazhagan, A.N., van Wijnen, A.J., Im, H.J. (2023). Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain. International Journal of Biological Sciences, 19(2), 675-690. https://doi.org/10.7150/ijbs.79125.

ACS

Ma, K.; Singh, G.; Wang, J.; O-Sullivan, I.; Votta-Velis, G.; Bruce, B.; Anbazhagan, A.N.; van Wijnen, A.J.; Im, H.J. Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain. Int. J. Biol. Sci. 2023, 19 (2), 675-690. DOI: 10.7150/ijbs.79125.

NLM

CSE

Ma K, Singh G, Wang J, O-Sullivan I, Votta-Velis G, Bruce B, Anbazhagan AN, van Wijnen AJ, Im HJ. 2023. Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain. Int J Biol Sci. 19(2):675-690.

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