Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.
Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.
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Mocetinostat激活Krüppel样因子4并保护骨关节炎中的组织破坏和炎症。
DOI：
10.1172/jci.insight.170513
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发表时间：
2023-09-08
期刊：
影响因子：
8
通讯作者：
Lotz, Martin K.
中科院分区：
文献类型：
--
作者：
Kawata, Manabu;McClatchy, Daniel B.;Diedrich, Jolene K.;Olmer, Merissa;Johnson, Kristen A.;Yates, John R.;Lotz, Martin K.
骨关节炎（OA）是最常见的关节疾病，疾病缓解OA药物（DMOAD）代表了OA管理的主要需求。Krüppel样因子4（KLF 4）是一种上调关节组织再生和保护功能的核心转录因子。本研究旨在鉴定激活KLF 4表达的小分子，并确定命中化合物的功能和机制。使用检测内源性KLF 4活化的报告细胞系对11，948种临床阶段化合物进行高通量筛选（HTS）。通过HTS鉴定了18种化合物，并在二次筛选中得到确认。在SW 1353软骨肉瘤细胞和人软骨细胞中进行测试后，mocetinostat -一种I类选择性组蛋白脱乙酰酶（HDAC）抑制剂-具有最佳的生物活性。Mocetinostat上调人软骨细胞、软骨细胞和BM源性间充质干细胞中的软骨特征基因，并下调这些细胞和滑膜细胞中的肥大、炎症和分解代谢基因。向小鼠腹膜内施用mocetinostat降低了OA相关变化的严重程度并改善了疼痛行为。全局基因表达和蛋白质组学分析显示，mocetinostat的再生和保护作用依赖于过氧化物酶体增殖物激活受体γ共激活因子1-α。这些发现显示了mocetinostat对OA的治疗和保护活性，使其有资格作为DMOAD的候选者。
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat — a class I selective histone deacetylase (HDAC) inhibitor — had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
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DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
对复发或难治性淋巴瘤中的组蛋白脱乙酰基酶抑制剂的2阶段研究。
影响因子：
6.5
作者：
Batlevi CL;Crump M;Andreadis C;Rizzieri D;Assouline SE;Fox S;van der Jagt RHC;Copeland A;Potvin D;Chao R;Younes A
通讯作者：
Younes A
影响因子：
4.8
作者：
Deuis JR;Dvorakova LS;Vetter I
通讯作者：
Vetter I
影响因子：
2.8
作者：
Krenn, V;Morawietz, L;König, A
通讯作者：
König, A
影响因子：
5
作者：
Carpio, Lomeli R.;Westendorf, Jennifer J.
通讯作者：
Westendorf, Jennifer J.