Background/Purpose: A disintegrin and metalloproteases (ADAMs) are reported that membrane-anchored glycoproteins composed of multiple distinct protein modules. ADAM-15 is one of them and is reported in several malignancies such as breast cancer and prostate cancer. However, the role of ADAM-15 in autoimmune diseases is unclear. Here, we have shown the role of ADAM-15 in rheumatoid arthritis (RA) angiogenesis.

Methods: RA and osteoarthritis (OA) synovial fluids (SFs) were obtained from patients. RA and normal (NL) serum were also obtained. ADAM-15 expression was measured in serum and SFs using enzyme-linked immuno sorbent assay (ELISA). To clarify the differences of ADAM-15 in RA treatment, the level of ADAM-15 at pre, 12, 24 and 54 weeks with tocilizumab treatment was measured. To determine ADAM-15 expression on RA synovial tissues, immunohistochemistry was performed. In order to examine the role of ADAM-15 in RA angiogenesis, we used human umbilical vein endothelial cells (HUVECs). To examine whether ADAM-15 was expressed on HUVECs, immunohistochemistry was also performed. To block the expression of ADAM-15, HUVECs were transfected with small interfering (si) RNA against ADAM-15. In order to confirm the role of angiogenesis, we did Matrigel assays in vitro. Finally, proangiogenic cytokines in ADAM-15 siRNA transfected HUVEC conditioned medium were measured.

Results: ADAM-15 in RA serum was significantly higher compared with NL (500 ± 21 pg/ml and 390 ± 29 pg/ml, respectively, p<0.05). The levels of ADAM-15 in RA SFs were also higher compared with OA SFs (619 ± 53 pg/ml and 328 ± 39 pg/ml, respectively, p<0.05). After treatment with tocilizumab, ADAM-15 in serum was significantly decreased between pre and 24 weeks (500 ± 21 pg/ml and 432 ± 21 pg/ml, respectively, p<0.05), pre and 54weeks (500 ± 21 pg/ml and 434 ± 22 pg/ml, respectively, p<0.05). We found that ADAM-15 was expressed on RA synovial tissue ECs and HUVECs. ADAM-15 siRNA treated HUVECs had decreased EC line and tube formed in Matrigel in response to RA SFs compared with non-treated HUVECs (number of EC lines 14 ± 2 and 7 ± 1, respectively, p<0.05) (number of EC tube formed 4 ± 1 and 1 ± 0, respectively, p<0.05). Epithelial neutrophil-activating protein 78 (ENA-78)/CXCL5 and intercellular adhesion molecule (ICAM) -1 in tumor necrosis factor (TNF) -α stimulated ADAM-15 siRNA transfected HUVEC conditioned medium were decreased compared with in TNF-α stimulated control siRNA transfected HUVEC conditioned medium.

Conclusion: These data show that ADAM-15 is expressed on RA synovial tissue ECs and may play a role in RA angiogenesis. ADAM-15 may be a potential target in inflammatory disease such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-disintegrin-and-metalloprotease-15-is-expressed-on-rheumatoid-arthritis-synovial-tissue-endothelial-cells-and-mediates-angiogenesis/