Mechanism of glycosaminoglycan-mediated bone and joint disease - Implications for the mucopolysaccharidoses and other connective tissue diseases
Mechanism of glycosaminoglycan-mediated bone and joint disease - Implications for the mucopolysaccharidoses and other connective tissue diseases
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DOI：
10.2353/ajpath.2008.070564
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Schuchman, Edward H.
中科院分区：
文献类型：
--
作者：
Simonaro, Calogera M.;D'Angelo, Marina;Schuchman, Edward H.
我们之前已经证明，在粘多糖病（NIPS）动物模型中，糖胺聚糖（GAG）的储存会导致软骨内的炎症和细胞凋亡。我们现在将这些发现扩展到滑膜组织，并进一步探索gag介导疾病的机制。对NIPS大鼠、猫和/或狗的分析显示，NIPS滑膜成纤维细胞和液体显示出许多炎症分子的表达升高，包括几种对脂多糖信号传导重要的蛋白质（例如toll样受体4和脂蛋白结合蛋白）。特别是肿瘤坏死因子的表达升高高达50倍，导致NIPS骨髓中破骨细胞存活因子、核因子- κ B配体受体激活因子上调，出现多核破骨细胞样细胞。用GAGS治疗正常滑膜成纤维细胞也导致促生存脂质鞘鞘醇-磷酸的产生，导致细胞增殖增强，与MPS患者滑膜组织增生一致。相反，正常软骨细胞的GAG处理导致促凋亡脂质神经酰胺的产生，证实了我们之前在MPS软骨中观察到的细胞死亡增强。这些发现对MPS的发病机制和治疗具有重要意义，并进一步明确了gag刺激疾病的机制。
We have previously shown that glycosaminoglycan (GAG) storage in animal models of the mucopolysaccharidoses (NIPS) leads to inflammation and apoptosis within cartilage. We have now extended these findings to synovial tissue and further explored the mechanism underlying GAG-mediated disease. Analysis of NIPS rats, cats, and/or dogs revealed that NIPS synovial fibroblasts and fluid displayed elevated expression of numerous inflammatory molecules, including several proteins important for lipopolysaccharide signaling (eg, Toll-like receptor 4 and lipoprotein binding protein). The expression of tumor necrosis factor, in particular, was elevated up to 50-fold, leading to up-regulation of the osteoclast survival factor, receptor activator of nuclear factor-kappa B ligand, and the appearance of multinucleated osteoclast-like cells in the NIPS bone marrow. Treatment of normal synovial fibroblasts with GAGS also led to production of the prosurvival lipid sphingosine-l-phosphate, resulting in enhanced cell proliferation, consistent with the hyperplastic synovial tissue observed in MPS patients. In contrast, GAG treatment of normal chondrocytes led to production of the proapoptotic lipid ceramide, confirming the enhanced cell death we had previously observed in MPS cartilage. These findings have important implications for the pathogenesis and treatment of MPS and have further defined the mechanism of GAG-stimulated disease.