Gene deletion of either interleukin-1β, interleukin-1β-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy
Gene deletion of either interleukin-1β, interleukin-1β-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy
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DOI：
10.1002/art.11355
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发表时间：
2003-12-01
影响因子：
--
通讯作者：
Mason, RM
中科院分区：
文献类型：
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作者：
Clements, KM;Price, JS;Mason, RM
客观的。在小鼠中内侧侧支韧带和部分内侧半月板切除术后骨关节炎（OA）的发展，其中编码介绍了interleukin-1beta（IL-1BETA），IL-1Beta转化酶（IL-1BETA）的基因，或者删除了诱导型一氧化氮合酶（INOS）。内侧侧支韧带和部分内侧半月板切除术的切片是在野生型和敲除小鼠的右膝关节上进行的。左关节用作无手术的对照。在手术后4天或1、2、3或4周的整个关节中，从整个关节中获得了串行组织学切片。将切片的OA病变分级为0-6，并通过基质金属蛋白酶（MMPS）（MMPS）（MMPS）和Aggrgrecanases对胫骨软骨基质蛋白聚糖（aggrecan）和II型胶原蛋白进行评估，并使用抗抗毒剂化学研究，使用抗杀菌剂，抗疫苗，抗疫苗，抗杀性剂，抗杀性，，抗活体化学研究和COI2-3/4C（短）NeoEpitope抗体。蛋白聚糖的耗竭是通过Alcian蓝色染色和软骨细胞死亡评估的，并通过Tunel Technique.Results评估。与野生型小鼠相比，所有敲除小鼠均显示手术后内侧软骨内侧软骨的OA病变的发育加速。冰膜，尤其是IL-1BETA-KNOCKOUT小鼠在无手术四肢的侧软骨中产生了OA病变。局灶性组织病理病变的发展伴随着MMP-，摄起酶 - 和胶原酶生成的裂解新皮上的水平升高，而在病变周围的地区，非经济状况却没有显示免疫染色的变化。在病变周围的焦点区域中，TUNEL染色也检测到了广泛的细胞死亡。我们假设每个基因的缺失，这些基因编码能够产生软骨变化的分子，导致调节合成代谢和分解代谢之间平衡的稳态控制的变化，有利于加速的软骨变性。这些观察结果表明，这些基因可能在保持关节软骨基质周转的正常稳态方面起重要的调节作用。
Objective. To investigate the development of osteoarthritis (OA) after transection of the medial collateral ligament and partial medial meniscectomy in mice in which genes encoding either interleukin-1beta (IL-1beta), IL-1beta-converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS) were deleted.Methods. Sectioning of the medial collateral ligament and partial medial meniscectomy were performed on right knee joints of wild-type and, knockout mice. Left joints served as unoperated controls. Serial histologic sections were obtained from throughout the whole joint of both knees 4 days or 1, 2, 3, or 4 weeks after surgery. Sections were graded for OA lesions on a scale of 0-6 and were assessed for breakdown of tibial cartilage matrix proteoglycan (aggrecan) and type II collagen by matrix metalloproteinases (MMPs) and aggrecanases with immunohistochemistry studies using anti-VDIPEN, anti-NITEGE, and CoI2-3/4C(short) neoepitope antibodies. Proteoglycan depletion was assessed by Alcian blue staining and chondrocyte cell death, with the TUNEL technique.Results. All knockout mice showed accelerated development of OA lesions in the medial tibial cartilage after surgery, compared with wild-type mice. ICE-iNOS-, and particularly IL-1beta-knockout mice developed OA lesions in the lateral cartilage of unoperated limbs. Development of focal histopathologic lesions was accompanied by increased levels of MMP-, aggrecanase-, and collagenase-generated cleavage neoepitopes in areas around lesions, while nonlesional areas showed no change in immunostaining. Extensive cell death was also detected by TUNEL staining in focal areas around lesions.Conclusion. We postulate that deletion of each of these genes, which encode molecules capable of producing degenerative changes in cartilage, leads to changes in the homeostatic controls regulating the balance between anabolism and catabolism, favoring accelerated cartilage degeneration. These observations suggest that these genes may play important regulatory roles in maintaining normal homeostasis in articular cartilage matrix turnover.