A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis.
A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis.
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一种VCP调节剂KUS 121，作为创伤后骨关节炎的有前途的治疗剂。
DOI：
10.1038/s41598-020-77735-2
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发表时间：
2020-11-27
影响因子：
4.6
通讯作者：
Matsuda S
中科院分区：
文献类型：
--
作者：
Saito M;Nishitani K;Ikeda HO;Yoshida S;Iwai S;Ji X;Nakahata A;Ito A;Nakamura S;Kuriyama S;Yoshitomi H;Murata K;Aoyama T;Ito H;Kuroki H;Kakizuka A;Matsuda S
创伤后骨关节炎（PTOA）是阻碍患者在关节内损伤或手术后恢复的主要原因。目前尚无有效的治疗方法。在这项研究中，我们发现抑制急性期软骨细胞死亡是一种很有希望的策略，以减轻PTOA的发展。也就是说，我们研究了京都大学物质（KUS） 121（一种含缬草苷的蛋白质调节剂）对toa的疗效及其治疗机制。在体内，在循环压缩载荷的大鼠PTOA模型中，与载体治疗相比，关节内KUS121治疗显著改善了改良的Mankin评分，减少了受损软骨体积。此外，KUS121显著减少损伤膝关节中TUNEL-、CHOP-、MMP-13-和adamts -5阳性软骨细胞的数量。在体外，KUS121在单层培养和软骨外植体中都能从tunicamycin诱导的细胞死亡中拯救人关节软骨细胞。它还显著下调内质网应激标志物、促炎细胞因子和由tunicamycin或IL-1β诱导的细胞外基质降解酶的蛋白或基因表达。总之，这些结果表明KUS121通过抑制过度内质网应激保护软骨细胞免于细胞死亡。因此，KUS121可能是一种新的、有前景的治疗药物，对PTOA的进展具有保护作用。
Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.
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影响因子：
13.3
作者：
Jackson, Miriam T.;Moradi, Babak;Little, Christopher B.
通讯作者：
Little, Christopher B.
影响因子：
4.6
作者：
Hasegawa T;Muraoka Y;Ikeda HO;Tsuruyama T;Kondo M;Terasaki H;Kakizuka A;Yoshimura N
通讯作者：
Yoshimura N
影响因子：
4
作者：
Nakano N;Ikeda HO;Hasegawa T;Muraoka Y;Iwai S;Tsuruyama T;Nakano M;Fuchigami T;Shudo T;Kakizuka A;Yoshimura N
通讯作者：
Yoshimura N
成年人类骨髓衍生，培养，合并，同种异体间质基质细胞（STEMPEUCEL®）的功效和安全性：膝关节骨关节炎中的临床前和临床试验。
影响因子：
4.9
作者：
Gupta PK;Chullikana A;Rengasamy M;Shetty N;Pandey V;Agarwal V;Wagh SY;Vellotare PK;Damodaran D;Viswanathan P;Thej C;Balasubramanian S;Majumdar AS
通讯作者：
Majumdar AS
影响因子：
--
作者：
Lewis, John S., Jr.;Furman, Bridgette D.;Zeitler, Evan;Huebner, Janet L.;Kraus, Virginia B.;Guilak, Farshid;Olson, Steven A.
通讯作者：
Olson, Steven A.