Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.
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.
Sensory & Motor System Medicine.
Shurei
S
Sugita
Sensory & Motor System Medicine, Bone and Cartilage Regenerative Medicine.
Yoko
Y
Hosaka
Sensory & Motor System Medicine.
Keita
K
Okada
Bone and Cartilage Regenerative Medicine.
Daisuke
D
Mori
Bone and Cartilage Regenerative Medicine, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
Fumiko
F
Yano
Sensory & Motor System Medicine.
Hiroshi
H
Kobayashi
Sensory & Motor System Medicine.
Yuki
Y
Taniguchi
Sensory & Motor System Medicine.
Yoshifumi
Y
Mori
Sensory & Motor System Medicine.
Tomotake
T
Okuma
Sensory & Motor System Medicine.
Song Ho
SH
Chang
Sensory & Motor System Medicine.
Manabu
M
Kawata
Sensory & Motor System Medicine.
Shuji
S
Taketomi
Sensory & Motor System Medicine.
Hirotaka
H
Chikuda
Department of Orthopaedics, Gifu University, Gifu 501-1194, Japan;
Haruhiko
H
Akiyama
Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; and.
Ryoichiro
R
Kageyama
Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
Ung-Il
UI
Chung
Sensory & Motor System Medicine.
Sakae
S
Tanaka
Sensory & Motor System Medicine, Spine Center, Tokyo Shinjuku Medical Center, Japan Community Health Care Organization, Shinjuku-ku, Tokyo 162-8543, Japan.
Hiroshi
H
Kawaguchi
Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
Shinsuke
S
Ohba
Sensory & Motor System Medicine, Bone and Cartilage Regenerative Medicine, tasaitou-tky@umin.ac.jp.
Taku
T
Saito
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse
CaMK2; Hes1; osteoarthritis