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Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5

Yoshifumi Takahata1, Eriko Nakamura1, Kenji Hata1

  • 1Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|July 18, 2018
PubMed

Insights

Sex-determining region Y-box 4 (Sox4) and Sox11 are involved in osteoarthritis onset. These transcription factors up-regulate ADAMTS4 and ADAMTS5, key enzymes in cartilage degradation, contributing to joint deterioration in osteoarthritis patients.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Rheumatology

Background:

  • Osteoarthritis (OA) pathogenesis is poorly understood, hindering the development of early diagnostic markers and effective treatments.
  • Identifying key molecular players, such as transcription factors, is crucial for understanding OA onset.

Purpose of the Study:

  • To identify transcription factors involved in the molecular mechanisms of osteoarthritis onset.
  • To investigate the role of Sox4 and Sox11 in the regulation of aggrecanases (ADAMTS4 and ADAMTS5) and cartilage destruction.

Main Methods:

  • Microarray analysis of mouse articular cartilage cells to identify differentially expressed genes.
  • Overexpression studies in chondrogenic cell lines (C3H10T1/2, SW1353) to assess the effect of Sox4 on ADAMTS gene expression.
  • Luciferase reporter and chromatin immunoprecipitation assays to determine Sox4's mechanism of action on gene promoters.
  • Organ culture experiments using mouse femoral head cartilages to evaluate the in vivo role of Sox4 and Sox11.
  • Quantitative analysis of SOX4 and SOX11 mRNA expression in human OA cartilage samples.

Main Results:

  • Retinoic acid up-regulated Sex-determining region Y-box 4 (Sox4) expression, along with aggrecanases ADAMTS4 and ADAMTS5, in mouse articular cartilage cells.
  • Sox4 overexpression induced ADAMTS4 and ADAMTS5 expression in chondrogenic cell lines.
  • Sox4 directly bound to the promoters of ADAMTS4 and ADAMTS5, up-regulating their gene activity.
  • Sox11, another SoxC family member, exhibited similar effects on ADAMTS expression.
  • Adenovirus-mediated Sox4 and Sox11 expression in mouse cartilage organ cultures led to cartilage destruction and increased Adamts5 expression.
  • SOX4 and SOX11 mRNA levels were significantly elevated in human osteoarthritis cartilage compared to non-osteoarthritic cartilage.

Conclusions:

  • Sox4 plays a significant role in osteoarthritis onset and cartilage deterioration by inducing the expression of ADAMTS4 and ADAMTS5.
  • Sox11 is also implicated in osteoarthritis pathogenesis through similar mechanisms.
  • These findings highlight Sox4 and Sox11 as potential therapeutic targets for osteoarthritis.
Keywords:
aggrecanaggrecanasearticular cartilageosteoarthritistranscription factor

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