Transcription factor Hes1 modulates osteoarthritis development

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K10461
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: TAKETOMI Syuji 東京大学, 医学部附属病院, 講師 (70570018)
• Co-Investigator(Kenkyū-buntansha): 乾 洋 東京大学, 医学部附属病院, 助教 (60583119) ; 矢野 文子 東京大学, 医学部附属病院, 特任講師 (80529040)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 変形性膝関節症 / Notch シグナル / Hes1

Outline of Final Research Achievements

Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors.
OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-CreERT;Hes1fl/fl mice. ChIP-seq identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding. 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.

Free Research Field

整形外科学