de Hooge Alfons S K, van de Loo Fons A J, Bennink Miranda B, Arntz Onno J, Fiselier Theo J W, Franssen Marcel J A M, Joosten Leo A B, Van Lent Peter L E M, Richards Carl D, van den Berg Wim B
Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
Arthritis Rheum. 2003 Jun;48(6):1750-61. doi: 10.1002/art.10972.
To investigate the involvement of proinflammatory and destructive mediators in oncostatin M (OSM)-induced joint pathology, using gene-deficient mice.
An adenoviral vector expressing murine OSM was injected into the joints of naive wild-type mice and mice deficient for interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNFalpha), or inducible nitric oxide synthase (iNOS). Reverse transcription-polymerase chain reaction was used to study gene expression. Inflammation and cartilage proteoglycan (PG) depletion were assessed by histology. OSM and IL-1 levels in synovial fluid from patients with juvenile idiopathic arthritis (JIA) were measured by enzyme-linked immunosorbent assay.
Adenoviral expression of murine OSM led to joint inflammation, bone apposition, chondrophyte formation, articular cartilage PG depletion, and VDIPEN neoepitope expression in wild-type mice. A unique and consistent observation was the focal PG depletion and disorganization of the growth plate cartilage during the first week of inflammation. Synovial IL-1beta, IL-6, TNFalpha, and iNOS gene expression was strongly induced. Of these factors, only deficiency in IL-1 markedly reduced inflammation and PG depletion and completely prevented growth plate damage. In addition, this is the first study in which OSM was detected in JIA synovial fluid. Most samples were also IL-1beta positive.
IL-1, but not IL-6, TNFalpha, or iNOS, plays an important role in joint disease induced by intraarticular gene transfer of OSM in mice. The effect of OSM on murine connective tissue and the presence of OSM in human synovial fluid make involvement of OSM in human arthropathies very likely.
利用基因缺陷小鼠研究促炎和破坏介质在制瘤素M（OSM）诱导的关节病变中的作用。
将表达小鼠OSM的腺病毒载体注射到未处理的野生型小鼠以及白细胞介素-1（IL-1）、IL-6、肿瘤坏死因子α（TNFα）或诱导型一氧化氮合酶（iNOS）基因缺陷的小鼠关节中。采用逆转录-聚合酶链反应研究基因表达。通过组织学评估炎症和软骨蛋白聚糖（PG）耗竭情况。采用酶联免疫吸附测定法测量幼年特发性关节炎（JIA）患者滑液中的OSM和IL-1水平。
小鼠OSM的腺病毒表达导致野生型小鼠出现关节炎症、骨附着、软骨细胞形成、关节软骨PG耗竭以及VDIPEN新表位表达。一个独特且一致的观察结果是在炎症的第一周生长板软骨出现局灶性PG耗竭和结构紊乱。滑膜IL-1β、IL-6、TNFα和iNOS基因表达被强烈诱导。在这些因子中，只有IL-1缺陷显著减轻了炎症和PG耗竭，并完全防止了生长板损伤。此外，这是首次在JIA滑液中检测到OSM的研究。大多数样本IL-1β也呈阳性。
在小鼠关节内基因转移OSM诱导的关节疾病中，IL-1而非IL-6、TNFα或iNOS发挥重要作用。OSM对小鼠结缔组织的作用以及其在人滑液中的存在使得OSM很可能参与人类关节病。
