Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses
Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses
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DOI：
10.1073/pnas.0912937107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Schuchman, Edward H.
中科院分区：
文献类型：
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作者：
Simonaro, Calogera M.;Ge, Yi;Schuchman, Edward H.
酶替代疗法目前可用于三种粘多糖（MPS），但对骨骼病变的影响有限。我们研究了Toll样受体4（TLR4）信号通路在MPS骨和关节疾病发病机制中的参与，以及抗TNF-α药物Remicade（Centocor，Inc.）接受治疗将TLR4 KO（TLR4（（lps-/-）小鼠与MPS VII小鼠杂交以产生双KO（DKO）动物。与MPS VII小鼠相比，DKO小鼠具有更长和更薄的面部以及更长的股骨，如通过显微计算机断层扫描分析所揭示的。组织学分析也显示了更有组织和更薄的生长板。在DKO动物中，TNF-α的血清水平被标准化，并且关节软骨细胞中磷酸化的STAT1和STAT3的水平被校正。这些结果使我们评价了类克在MPS VI大鼠中的作用。当在1月龄时开始静脉注射治疗时，不仅在血液中，而且在关节软骨细胞和成纤维细胞样滑膜细胞（FLS）中，静脉注射治疗防止了TNF-α、NF-κ B受体激活剂和其他炎症分子的升高。对6个月大的动物进行治疗也将这些分子的水平降低到正常水平。MPS VI大鼠中凋亡关节软骨细胞的数量也同样减少，滑膜组织向下层骨的浸润较少。这些研究揭示了TLR4信号在MPS骨和关节疾病中的重要作用，并表明靶向TNF-α可能具有积极的治疗效果。
Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-alpha drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4((lps-/-))) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-alpha were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-alpha, receptor activator of NF-kappa B, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-month-old animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-alpha may have positive therapeutic effects.