Anti-TNF-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type VI.
Anti-TNF-alpha therapy enhances the effects of enzyme replacement therapy in rats with mucopolysaccharidosis type VI.
复制标题
DOI：
10.1371/journal.pone.0022447
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Simonaro CM
中科院分区：
文献类型：
--
作者：
Eliyahu E;Wolfson T;Ge Y;Jepsen KJ;Schuchman EH;Simonaro CM
虽然酶替代疗法（ERT）可用于几种溶酶体储存疾病，但这种治疗对骨骼系统的益处非常有限。我们之前的工作已经表明toll样受体4/ tnf - α炎症通路在粘多糖病（MPS）的骨骼病理中的重要性，因此我们进行了一项研究，以检验在粘多糖病（MPS） VI型大鼠模型中联合抗tnf - α治疗与ERT的附加益处。MPS VI大鼠用Naglazyme®（重组人n -乙酰半乳糖胺-4-硫酸酯酶）治疗8个月。或使用Naglazyme®和大鼠特异性抗tnf - α药物CNTO1081的联合方案。两种治疗方案均显著降低血清tnf - α水平和RANKL，尽管只有联合治疗降低了关节软骨中的tnf - α。对培养的关节软骨细胞的分析显示，联合治疗还恢复了胶原IIA1的表达，并降低了凋亡标志物PARP的表达。ERT改善了运动活动和机动性，联合治疗显著增强了这些。MPS VI动物的气管畸形仅通过联合治疗得到改善，骨长度也有适度改善。气管中的神经酰胺水平也明显降低。MicroCT分析没有显示两种治疗对骨微结构有任何显著的积极影响，也没有骨生长板的组织学改善。结果表明ERT联合抗tnf - α治疗改善了治疗效果，临床获益显著。他们还进一步验证了tnf - α、RANKL和其他炎症分子作为MPS疾病生物标志物的有效性。在其他MPS动物模型和患者中进一步评估这种联合方法是有必要的。
Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI. MPS VI rats were treated for 8 months with Naglazyme® (recombinant human N-acetyl-galactosamine-4-sulfatase), or by a combined protocol using Naglazyme® and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities in the MPS VI animals were only improved by combination therapy, and there was a modest improvement in bone length. Ceramide levels in the trachea also were markedly reduced. MicroCT analysis did not demonstrate any significant positive effects on bone microarchitecture from either treatment, nor was there histological improvement in the bone growth plates. The results demonstrate that combining ERT with anti-TNF- alpha therapy improved the treatment outcome and led to significant clinical benefit. They also further validate the usefulness of TNF-alpha, RANKL and other inflammatory molecules as biomarkers for the MPS disorders. Further evaluation of this combination approach in other MPS animal models and patients is warranted.
登录
查看更多内容
影响因子：
3.6
作者：
Wraith, J. Edmond;Scarpa, Maurizio;Beck, Michael;Bodamer, Olaf A.;De Meirleir, Linda;Guffon, Nathalie;Lund, Allan Meldgaard;Malm, Gunilla;Van der Ploeg, Ans T.;Zeman, Jiri
通讯作者：
Zeman, Jiri
影响因子：
6.2
作者：
Simonardo, CM;Haskins, ME;Schuchman, EH
通讯作者：
Schuchman, EH
影响因子：
1.9
作者：
Decker, Celeste;Yu, Zi-Fan;Harmatz, Paul
通讯作者：
Harmatz, Paul
影响因子：
6.2
作者：
Clarke, Lorne A.
通讯作者：
Clarke, Lorne A.
影响因子：
6
作者：
Simonaro, Calogera M.;D'Angelo, Marina;Schuchman, Edward H.
通讯作者：
Schuchman, Edward H.