Anti–neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis
Jin-Sun Kong
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorSeung-Ah Yoo
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorJung-Wook Kim
Pohang University of Science and Technology, Pohang, South Korea
Search for more papers by this authorValeria Tarallo
Consiglio Nazionale delle Ricerche, Naples, Italy
Search for more papers by this authorSandro De Falco
Consiglio Nazionale delle Ricerche, Naples, Italy
Search for more papers by this authorSung-Ho Ryu
Pohang University of Science and Technology, Pohang, South Korea
Search for more papers by this authorChul-Soo Cho
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Wan-Uk Kim
The Catholic University of Korea, Seoul, South Korea
Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, St. Vincent's Hospital, 93 Chi-Dong, Suwon 442-723, South KoreaSearch for more papers by this authorJin-Sun Kong
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorSeung-Ah Yoo
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorJung-Wook Kim
Pohang University of Science and Technology, Pohang, South Korea
Search for more papers by this authorValeria Tarallo
Consiglio Nazionale delle Ricerche, Naples, Italy
Search for more papers by this authorSandro De Falco
Consiglio Nazionale delle Ricerche, Naples, Italy
Search for more papers by this authorSung-Ho Ryu
Pohang University of Science and Technology, Pohang, South Korea
Search for more papers by this authorChul-Soo Cho
The Catholic University of Korea, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Wan-Uk Kim
The Catholic University of Korea, Seoul, South Korea
Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, St. Vincent's Hospital, 93 Chi-Dong, Suwon 442-723, South KoreaSearch for more papers by this authorAbstract
Objective
To delineate the role of neuropilin-1 (NP-1), a vascular endothelial growth factor receptor (VEGFR), in rheumatoid inflammation and to determine whether blockade of NP-1 could suppress synoviocyte survival and angiogenesis.
Methods
VEGF111–165 peptide, which encompasses the NP-1 binding domain of VEGF165, was generated by cleaving VEGF165 with plasmin. The effect of this peptide on the interaction between VEGF165 and its receptor was determined by 125I-VEGFR binding assay. Assays to determine synoviocyte apoptosis, adhesion, and migration were performed in the presence of VEGF165 and/or the peptide. VEGF165-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of endothelial cells (ECs). Mice were immunized with type II collagen to induce experimental arthritis.
Results
VEGF111–165 peptide specifically inhibited the binding of 125I-VEGF165 to NP-1 on rheumatoid synoviocytes and ECs. The peptide eliminated the VEGF165-mediated increase in synoviocyte survival and activation of p-ERK and Bcl-2. The peptide also completely inhibited a VEGF165-induced increase in synoviocyte adhesion and migration. In addition, the anti–NP-1 peptide blocked VEGF165-stimulated proliferation, capillary tube formation, and wounding migration of ECs in vitro. VEGF165-induced neovascularization in a Matrigel plug in mice was also blocked by treatment with the peptide. Finally, subcutaneous injection of anti–NP-1 peptide suppressed arthritis severity and autoantibody formation in mice with experimental arthritis and inhibited synoviocyte hyperplasia and angiogenesis in arthritic joints.
Conclusion
Anti–NP-1 peptide suppressed VEGF165-induced increases in synoviocyte survival and angiogenesis, and thereby blocked experimental arthritis. Our findings suggest that anti–NP-1 peptide could be useful in alleviating chronic arthritis.
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