Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.
Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.
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DOI：
10.1126/scitranslmed.aaa4616
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发表时间：
2015-05-20
影响因子：
17.1
通讯作者：
Bottini N
中科院分区：
文献类型：
--
作者：
Doody KM;Stanford SM;Sacchetti C;Svensson MN;Coles CH;Mitakidis N;Kiosses WB;Bartok B;Fos C;Cory E;Sah RL;Liu-Bryan R;Boyle DL;Arnett HA;Mustelin T;Corr M;Esko JD;Tremblay ML;Firestein GS;Aricescu AR;Bottini N
尽管有几种针对免疫系统的类风湿性关节炎（RA）治疗方法，但大量RA患者未能达到缓解。关节衬里细胞，称为成纤维细胞样滑膜细胞（FLS），在RA期间被激活并介导关节炎症和软骨和骨的破坏。我们确定RPTPσ，一种跨膜酪氨酸磷酸酶，作为FLS导向治疗的治疗靶点。RPTPσ通过与含有细胞外蛋白聚糖的硫酸软骨素或硫酸乙酰肝素的相互作用在称为蛋白聚糖开关的机制中被间接调节。我们表明，蛋白聚糖开关调节FLS功能。将FLS与蛋白聚糖结合RPTPσ诱饵蛋白孵育，通过破坏RPTPσ和硫酸乙酰肝素蛋白聚糖syndecan-4之间的组成性相互作用来抑制细胞侵袭和附着于软骨。RPTPσ通过调节ezrin的磷酸化和细胞骨架定位介导蛋白多糖对FLS信号传导的影响。此外，在RA的K/BxN血清转移模型中，施用RPTPσ诱饵蛋白改善了体内人FLS侵袭性和关节炎严重程度。我们的数据表明，FLS在体内受RPTPσ依赖性蛋白聚糖开关的调节，这可以作为RA治疗的靶点。我们设想，针对FLS中蛋白聚糖开关或其细胞内途径的治疗可以有效地作为单一疗法或与目前可用的免疫靶向药物组合，以改善RA患者疾病活动的控制。
Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.
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影响因子：
4.8
作者：
Müller, T;Choidas, A;Ullrich, A
通讯作者：
Ullrich, A
影响因子：
3.8
作者：
Mak H;Naba A;Varma S;Schick C;Day A;SenGupta SK;Arpin M;Elliott BE
通讯作者：
Elliott BE
类风湿关节炎中滑膜细胞。滑膜成纤维细胞。
影响因子：
4.9
作者：
Mueller-Ladner, Ulf;Ospelt, Caroline;Gay, Steffen;Distler, Oliver;Pap, Thomas
通讯作者：
Pap, Thomas
影响因子：
7.3
作者：
Duan, Yuntao;Giger, Roman J.
通讯作者：
Giger, Roman J.
影响因子：
27.4
作者：
Korb-Pap, Adelheid;Stratis, Athanasios;Redlich, Kurt
通讯作者：
Redlich, Kurt