RRC ID 36901
著者 Sugita S, Hosaka Y, Okada K, Mori D, Yano F, Kobayashi H, Taniguchi Y, Mori Y, Okuma T, Chang SH, Kawata M, Taketomi S, Chikuda H, Akiyama H, Kageyama R, Chung UI, Tanaka S, Kawaguchi H, Ohba S, Saito T.
タイトル Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.
ジャーナル Proc Natl Acad Sci U S A
Abstract 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 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ 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 CaMK2δ 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.
巻・号 112(10)
ページ 3080-5
公開日 2015-3-10
DOI 10.1073/pnas.1419699112
PII 1419699112
PMID 25733872
PMC PMC4364241
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / metabolism Basic Helix-Loop-Helix Transcription Factors / physiology* Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism* Gene Expression Regulation HEK293 Cells HeLa Cells Homeodomain Proteins / metabolism Homeodomain Proteins / physiology* Humans Mice Mice, Inbred C57BL Mice, Transgenic Osteoarthritis / enzymology Osteoarthritis / metabolism Osteoarthritis / physiopathology* Transcription Factor HES-1 Transcription, Genetic
IF 9.412
引用数 36
WOS 分野 MULTIDISCIPLINARY SCIENCES
リソース情報
ヒト・動物細胞 HeLa ATDC5(RCB0565)