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Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
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Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness

Published on: March 18, 2022

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

Shurei Sugita1, Yoko Hosaka2, Keita Okada1

  • 1Sensory & Motor System Medicine.

Proceedings of the National Academy of Sciences of the United States of America
|March 4, 2015
PubMed

Insights

Hes1, a Notch signaling target, drives osteoarthritis (OA) by inducing cartilage-degrading enzymes. Deleting Hes1 in adult articular cartilage suppressed OA, revealing Hes1 and CaMK2δ as key targets for joint disorder treatments.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • Notch signaling influences skeletal development and osteoarthritis (OA) pathogenesis by promoting catabolic factors.
  • Hes1, a transcription factor and key Notch signaling target, plays a role in these processes.

Purpose of the Study:

  • To investigate the specific roles of Hes1 in osteoarthritis development and pathogenesis.
  • To elucidate the molecular mechanisms by which Hes1 modulates cartilage catabolism.

Main Methods:

  • Generation of tissue-specific Hes1 deletion mouse models (Sox9-Cre and Col2a1-Cre(ERT);Hes1(fl/fl)).
  • In vitro studies using cultured chondrocytes.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) and luciferase assays to identify Hes1 target genes.
  • Microarray analysis to discover novel Hes1 targets.
  • Identification of Hes1 cofactors using biochemical assays.

Main Results:

  • Deletion of Hes1 in adult articular cartilage suppressed OA development.
  • Hes1 directly induced catabolic enzymes Adamts5 and Mmp13 in chondrocytes.
  • Novel Hes1 target genes, including Il6 and Il1rl1, were identified.
  • CaMK2δ was identified as a cofactor that switches Hes1 from a repressor to an activator, inducing cartilage catabolic factors.

Conclusions:

  • Hes1, in cooperation with CaMK2δ, promotes OA pathogenesis by inducing catabolic factors like Adamts5, Mmp13, Il6, and Il1rl1.
  • Targeting the Hes1-CaMK2δ pathway may offer novel therapeutic strategies for osteoarthritis and other joint disorders.
Keywords:
CaMK2Hes1osteoarthritis

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