Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia

Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the joints and their lining or synovium. Previous studies showed that the synovium in RA patients is more hypoxic than normal synovium. Activated protein C (APC) has anticoagulant and anti-inflammatory effects and is hig...

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Main Authors:	Park, Yang-Gyu, Choi, Jawun, Song, Inkyu, Jackson, Christopher J., Park, Sang-Youel, Seol, Jae-Won
Format:	Article
Language:	English
Published:	Penerbit Universiti Kebangsaan Malaysia 2017
Online Access:	http://journalarticle.ukm.my/11549/ http://journalarticle.ukm.my/11549/ http://journalarticle.ukm.my/11549/1/28%20Yang-Gyu%20Park.pdf

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spelling	ukm-115492018-04-10T10:05:13Z http://journalarticle.ukm.my/11549/ Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia Park, Yang-Gyu Choi, Jawun Song, Inkyu Jackson, Christopher J. Park, Sang-Youel Seol, Jae-Won Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the joints and their lining or synovium. Previous studies showed that the synovium in RA patients is more hypoxic than normal synovium. Activated protein C (APC) has anticoagulant and anti-inflammatory effects and is highly expressed in the joints of RA patients. We examined the effect of APC on RA and normal synovial fibroblasts under hypoxic conditions. Human synovial fibroblasts were isolated from the synovial tissues of RA patients and normal controls and cells were exposed to recombinant APC under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions. Cell proliferation was measured using MTT assays. Cell lysates and conditioned media were collected and assayed for matrix metalloproteinase (MMP)-2, MMP-9 and p38 using zymography and western blots. Proliferation of both normal and RA synovial fibroblasts dose-dependently increased after APC treatment in normoxic conditions. Under hypoxia, APC enhanced RA cell proliferation but had no effect on normal fibroblasts. MMP-2 production and activation were significantly augmented by APC in both cell types under normoxia and hypoxia conditions. However, activated MMP-2 was more reduced in cells under hypoxia than normoxia. APC substantially reduced the phosphorylation of p38 in normal and RA synovial fibroblasts under hypoxia. No difference in p38 phosphorylation was observed under normoxia. The receptor for APC, endothelial protein C receptor (EPCR), was elevated in normal fibroblasts under hypoxic conditions whereas in RA cells, EPCR was highly expressed under both normoxic and hypoxic conditions. We found that hypoxia enhanced the effect of APC on RA synovial fibroblasts through activation of MMP2 and inhibition of p38 phosphorylation. Our results suggested that APC may suppress joint destruction and progression of inflammation in a hypoxic RA environment. Penerbit Universiti Kebangsaan Malaysia 2017-10 Article PeerReviewed application/pdf en http://journalarticle.ukm.my/11549/1/28%20Yang-Gyu%20Park.pdf Park, Yang-Gyu and Choi, Jawun and Song, Inkyu and Jackson, Christopher J. and Park, Sang-Youel and Seol, Jae-Won (2017) Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia. Sains Malaysiana, 46 (10). pp. 1895-1902. ISSN 0126-6039 http://www.ukm.my/jsm/english_journals/vol46num10_2017/contentsVol46num10_2017.html
repository_type	Digital Repository
institution_category	Local University
institution	Universiti Kebangasaan Malaysia
building	UKM Institutional Repository
collection	Online Access
language	English
description	Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the joints and their lining or synovium. Previous studies showed that the synovium in RA patients is more hypoxic than normal synovium. Activated protein C (APC) has anticoagulant and anti-inflammatory effects and is highly expressed in the joints of RA patients. We examined the effect of APC on RA and normal synovial fibroblasts under hypoxic conditions. Human synovial fibroblasts were isolated from the synovial tissues of RA patients and normal controls and cells were exposed to recombinant APC under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions. Cell proliferation was measured using MTT assays. Cell lysates and conditioned media were collected and assayed for matrix metalloproteinase (MMP)-2, MMP-9 and p38 using zymography and western blots. Proliferation of both normal and RA synovial fibroblasts dose-dependently increased after APC treatment in normoxic conditions. Under hypoxia, APC enhanced RA cell proliferation but had no effect on normal fibroblasts. MMP-2 production and activation were significantly augmented by APC in both cell types under normoxia and hypoxia conditions. However, activated MMP-2 was more reduced in cells under hypoxia than normoxia. APC substantially reduced the phosphorylation of p38 in normal and RA synovial fibroblasts under hypoxia. No difference in p38 phosphorylation was observed under normoxia. The receptor for APC, endothelial protein C receptor (EPCR), was elevated in normal fibroblasts under hypoxic conditions whereas in RA cells, EPCR was highly expressed under both normoxic and hypoxic conditions. We found that hypoxia enhanced the effect of APC on RA synovial fibroblasts through activation of MMP2 and inhibition of p38 phosphorylation. Our results suggested that APC may suppress joint destruction and progression of inflammation in a hypoxic RA environment.
format	Article
author	Park, Yang-Gyu Choi, Jawun Song, Inkyu Jackson, Christopher J. Park, Sang-Youel Seol, Jae-Won
spellingShingle	Park, Yang-Gyu Choi, Jawun Song, Inkyu Jackson, Christopher J. Park, Sang-Youel Seol, Jae-Won Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
author_facet	Park, Yang-Gyu Choi, Jawun Song, Inkyu Jackson, Christopher J. Park, Sang-Youel Seol, Jae-Won
author_sort	Park, Yang-Gyu
title	Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
title_short	Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
title_full	Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
title_fullStr	Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
title_full_unstemmed	Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia
title_sort	differential effects of activated protein c on synovial fibroblasts in response to hypoxia and normoxia
publisher	Penerbit Universiti Kebangsaan Malaysia
publishDate	2017
url	http://journalarticle.ukm.my/11549/ http://journalarticle.ukm.my/11549/ http://journalarticle.ukm.my/11549/1/28%20Yang-Gyu%20Park.pdf
first_indexed	2023-09-18T20:00:36Z
last_indexed	2023-09-18T20:00:36Z
_version_	1777406822518358016

Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia

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