Rowan A D, Koshy P J, Shingleton W D, Degnan B A, Heath J K, Vernallis A B, Spaull J R, Life P F, Hudson K, Cawston T E
Rheumatology, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK.
Arthritis Rheum. 2001 Jul;44(7):1620-32. doi: 10.1002/1529-0131(200107)44:7<1620::AID-ART285>3.0.CO;2-B.
To determine whether other glycoprotein 130 (gp130) binding cytokines can mimic the effects of oncostatin M (OSM) in acting synergistically with interleukin-1alpha (IL-1alpha) to induce cartilage collagen breakdown and collagenase expression, and to determine which receptors mediate these effects.
The release of collagen and proteoglycan was assessed in bovine and human cartilage explant cultures. Messenger RNA (mRNA) and protein production from immortalized human chondrocytes (T/C28a4) was analyzed by Northern blotting and specific enzyme-linked immunosorbent assays. Collagenase activity was measured by bioassay. Cell surface receptors were detected by flow cytometry.
OSM in combination with IL-1alpha caused a rapid synergistic induction of matrix metalloproteinase 1 mRNA, which was sustained over a 72-hour period. Flow cytometric analyses detected both the OSM-specific receptor and the gp130 receptor at the chondrocyte cell surface, but failed to detect the leukemia inhibitory factor receptor (LIFR). Cartilage degradation assays revealed that, of the gp130 binding cytokines, only OSM and IL-6, in the presence of its soluble receptor (sIL-6R), were able to act synergistically with IL-1alpha to promote collagen release.
This study demonstrates that IL-6 can mimic OSM in synergizing with IL-1alpha to induce chondrocyte-mediated cartilage collagen breakdown and collagenase production. In order to have this effect, IL-6 requires the presence of its soluble receptor. The apparent absence of LIFR explains why other gp130 binding cytokines do not act in synergy with IL-1alpha. Since OSM, IL-6, and sIL-6R levels have all been shown to be elevated in the rheumatoid joint, our findings suggest that these cytokines may be key mediators of cartilage collagen catabolism in the inflammatory arthritides.
确定其他糖蛋白130（gp130）结合细胞因子是否能模拟抑瘤素M（OSM）与白细胞介素-1α（IL-1α）协同作用诱导软骨胶原降解和胶原酶表达的效应，并确定介导这些效应的受体。
在牛和人软骨外植体培养物中评估胶原和蛋白聚糖的释放。通过Northern印迹法和特异性酶联免疫吸附测定法分析永生化人软骨细胞（T/C28a4）的信使核糖核酸（mRNA）和蛋白质产生。通过生物测定法测量胶原酶活性。通过流式细胞术检测细胞表面受体。
OSM与IL-1α联合使用可迅速协同诱导基质金属蛋白酶1 mRNA，这种诱导在72小时内持续存在。流式细胞术分析在软骨细胞表面检测到了OSM特异性受体和gp130受体，但未检测到白血病抑制因子受体（LIFR）。软骨降解试验表明，在gp130结合细胞因子中，只有OSM和白细胞介素-6（IL-6）在其可溶性受体（sIL-6R）存在的情况下，能够与IL-1α协同作用促进胶原释放。
本研究表明，IL-6可模拟OSM与IL-1α协同作用，诱导软骨细胞介导的软骨胶原降解和胶原酶产生。为产生这种效应，IL-6需要其可溶性受体的存在。LIFR明显缺失解释了为什么其他gp130结合细胞因子不能与IL-1α协同作用。由于已证明类风湿关节中OSM、IL-6和sIL-6R水平均升高，我们的研究结果表明，这些细胞因子可能是炎性关节炎中软骨胶原分解代谢的关键介质。
