Blockade of vascular endothelial growth factor receptor-1 (Flt-1), reveals a novel analgesic for osteoarthritis-induced joint pain
Autor: | Thomas J. Park, Jeffrey S. Kroin, Daniel T. Applegate, Bronislaw Pytowski, Richard Ripper, Xin Li, In Sug O-Sullivan, Andre J. van Wijnen, Gina Votta-Velis, Ranjan Kc, Hee Jeong Im, Vaskar Das |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
business.industry Analgesic Osteoarthritis Pharmacology medicine.disease Article Vascular endothelial growth factor 03 medical and health sciences chemistry.chemical_compound Vascular endothelial growth factor A 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Allodynia Dorsal root ganglion chemistry Joint pain cardiovascular system Genetics medicine medicine.symptom business 030217 neurology & neurosurgery Blood vessel |
Zdroj: | Gene Reports. 11:94-100 |
ISSN: | 2452-0144 |
Popis: | Osteoarthritis (OA) is a painful and debilitating disease. A striking feature of OA is the dramatic increase in vascular endothelial growth factor (VEGF) levels and in new blood vessel formation in the joints, both of which correlate with the severity of OA pain. Our aim was to determine whether anti-VEGF monoclonal antibodies (mAbs) – MF-1 (mAb to VEGFR1) and DC101 (mAb to VEGFR2) – can reduce OA pain and can do so by targeting VEGF signaling pathways such as Flt-1 (VEGFR1) and Flk-1 (VEGFR2). After IACUC approval, OA was induced by partial medial meniscectomy (PMM) in C57/BL6 mice (20 g). ln the first experiment, for validation of VEGFR1 in DRG, the mouse dorsal root ganglion (DRG) was stimulated with NGF for 48 hours to find the relative gene induction for VEGFR1 vs. 18S by RT-PCR. In the second experiment, Biotin-conjugated VEGFA (1 µg/knee joint) was administered in the left knee joint of mice with advanced OA in order to characterization of VEGFR1 and VEGFR2. pVEGFR1/VEGFR2 was detected by immunostaining in DRGs. Finally, MF-1 and DC101 were administered in OA mice by both intrathecal (IT) and intraarticular (IA) injections, and the change in paw withdrawal threshold (PWT) was measured. Retrograde transport of VEGF was confirmed for detection of pVEGFR1/VEGFR2 in the DRG. PMM surgery led to development of OA and mechanical allodynia, with reduced paw withdrawal thresholds (PWT) (P |
Databáze: | OpenAIRE |
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