Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
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The Effects of Heme Oxygenase-1 on Collagen Induced Arthritis Model

콜라겐 유도 관절염 모델에서 HO-1의 역할에 관한 연구

Jang, Seong-Jo;Kim, Yu-Rim;Choe, Eun-Yeong;Lee, Eun-Gyeong;Kim, Gyeong-Suk;Gwon, Deok-Su;O, Jae-Min;Choe, Min-Gyu;Lee, Byeong-Gi;Yang, Chung-Yong;Kim, Jeong-U;Jeon, Cheol-Hong;Song, Ha-Heon;Kim, Heon-Su;Yun, Gi-Jung;Lee, Myeong-Su
장성조;김유림;최은영;이은경;김경숙;권덕수;오재민;최민규;이병기;양충용;김정우;전철홍;송하헌;김헌수;윤기중;이명수

  • Published : 20060000
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Abstract

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to inflammatory stresses. It has been known to show strong immunosuppressive properties although its mechanisms are not completely understood. This study was designed to determine the effects of HO-1 modulation on collagen induced arthritis (CIA) model. CIA model was induced by subcutaneous injection of collagen on tail of DBA/1J mice. For evaluation of HO-1 effects, an inducer of HO-1, cobalt protoporphyrin IX (CoPPIX), or an inhibitor of HO-1, tin protoporphyrin IX (SnPPIX), were administered every other days into peritoneal cavity from day 1 to day 42 after CIA induction. The macrocopic clinical findings of CIA were evaluated and histo-pathologic findings and radiographic analysis were carried out. The expressions of TNF-α, IL-6, and VEGF which have important roles in pathogenesis of rheumatoid arthritis were observed by immuno-histochemical staining. Collagen on DBA/1J mice induced arthritis at knee joint and ankle joint. Administration of CoPPIX significantly aggravated the severity of arthritis while SnPPIX protected collagen induced arthritis. SnPPIX strongly suppressed inflammatory cell infiltration, swelling of synovial membrane, and erosion and destruction of bone on CIA mice. Furthermore subcutaneous injection of collagen also increased expression of TNF-α, IL-6, and VEGF which are important pro-inflammatory mediators in rheumatoid arthritis. SnPPIX suppressed expression of the pro-inflammatory mediators on CIA mice. Finally, we suggest that HO-1 mediates the expression of pro-inflammatory mediators and bone destruction during pathogenesis of CIA, which indicates modulation of HO-1 can be a new therapeutic target of rheumatoid arthritis.

Heme oxygenase-1 (HO-1)은 heme을 대사 시키는 효소로서 염증성 자극에 대한 반응으로 발현되고 항염작용이 있는 것으로 알려져 있지만 그 작용 기전에 대한 연구는 미흡한 실정이다. 따라서 본 연구는 콜라겐 으로 유도된 관절염 모델(collagen induced arthritis, CIA)에서 HO-1의 역할을 알아보기 위하여 수행되었다. DBA/1J 생쥐의 꼬리에 콜라겐을 피하 주사하여 관절염을 유도하였다. CIA 생쥐에서 HO-1의 효과를 분석하기 위하여 HO-1의 유도제인 cobalt protoporphyrin IX (CoPPIX)와 저해제인 tin protoporphyrin IX (SnPPIX)를 관절 염 유도 첫날부터 42일까지 복강에 2일마다 주사하여 관절염이 유발되는 상황을 관찰하였다. 관절염의 유발 정 도는 육안으로 평가되었고 염증의 진행정도와 뼈의 손상정도는 관절의 병리조직학적 관찰과 방사선적 검사를 통하여 관찰하였다. 또한 관절염의 병리과정에 중요한 역할을 하는 TNF-α, IL-6, VEGF 등 염증매개물질들의 발 현은 면역조직화학검사를 통하여 분석하였다. DBA/1J 생쥐의 꼬리에 콜라겐을 피하 주사하였을 때 무릎관절과 발목관절이 부으면서 관절염이 유도되었다. CoPPIX를 처리한 군 (CoPPIX군)은 CIA군에 비하여 관절염의 유발정도가 심한 반면, SnPPIX를 처리한 군 (SnPPIX군)에서는 관절염이 현저히 억제되었다. 관절의 조직학적인 소견에서도 콜라겐에 의한 세포의 침윤, 활 막의 비후, 연골과 골의 미란 및 파괴 등이 SnPPIX처리에 의하여 개선되었다. 또한 콜라겐에 의하여 류마티스성 관절염에서 중요한 역할을 하는 TNF-α, IL-6, VEGF 등의 염증 매개물질들의 발현의 증가도 CoPPIX군에서는 증가한 반면 SnPPIX군에서는 억제되었다. 결론적으로 HO-1이 CIA의 병리과정에서 염증 매개물질의 발현을 촉 진 시키고 골 손상을 악화시키는 것으로 생각되었고, 이는 HO-1의 발현의 조절이 류마티스성 관절염의 치료에 새로운 치료 목표가 될 수 있음을 제시한다고 생각한다.

Keywords

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