Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2

被引:99
作者
Sugita, Shurei [1 ]
Hosaka, Yoko [1 ]
Okada, Keita [1 ]
Mori, Daisuke [1 ]
Yano, Fumiko [1 ,2 ]
Kobayashi, Hiroshi [1 ]
Taniguchi, Yuki [1 ]
Mori, Yoshifumi [1 ]
Okuma, Tomotake [1 ]
Chang, Song Ho [1 ]
Kawata, Manabu [1 ]
Taketomi, Shuji [1 ]
Chikuda, Hirotaka [1 ]
Akiyama, Haruhiko [3 ]
Kageyama, Ryoichiro [4 ]
Chung, Ung-il [2 ]
Tanaka, Sakae [1 ]
Kawaguchi, Hiroshi [1 ,5 ]
Ohba, Shinsuke [2 ]
Saito, Taku [1 ]
机构
[1] Univ Tokyo, Fac Med, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Fac Med, Ctr Dis Biol & Integrat Med, Bunkyo Ku, Tokyo 1138655, Japan
[3] Gifu Univ, Dept Orthopaed, Gifu 5011194, Japan
[4] Kyoto Univ, Inst Virus Res, Sakyo Ku, Kyoto 6068507, Japan
[5] Japan Community Hlth Care Org, Tokyo Shinjuku Med Ctr, Spine Ctr, Shinjuku Ku, Tokyo 1628543, Japan
关键词
osteoarthritis; Hes1; CaMK2; ENDOCHONDRAL OSSIFICATION; CARTILAGE DEGRADATION; RHEUMATOID-ARTHRITIS; DISEASE-ACTIVITY; SYNOVIAL-FLUID; C/EBP-BETA; INTERLEUKIN-6; GROWTH; CHONDROCYTES; ADAMTS5;
D O I
10.1073/pnas.1419699112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT); Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2 delta (CaMK2 delta) as a cofactor of Hes1; CaMK2 delta was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2 delta to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
引用
收藏
页码:3080 / 3085
页数:6
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