HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells

Nobuyuki Fujita, Yuichiro Hirose, Cassie M. Tran, Kazuhiro Chiba, Takeshi Miyamoto, Yoshiaki Toyama, Irving M. Shapiro, Makarand V. Risbud

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Intervertebral disc degeneration is the leading cause of chronic back pain. Recent studies show that raised level of SDC4, a cell-surface heparan sulfate (HS) proteoglycan, plays a role in pathogenesis of disc degeneration. However, in nucleus pulposus (NP) cells of the healthy intervertebral disc, the mechanisms that control expression of SDC4 and its physiological function are unknown. Hypoxia induced SDC4 mRNA and protein expression by ∼2.4- and 4.4-fold (P<0.05), respectively, in NP cells. While the activity of the SDC4 promoter containing hypoxia response element (HRE) was induced 2-fold (P<0.05), the HRE mutation decreased the activity by 40% in hypoxia. Transfections with plasmids coding prolyl-4-hydroxylase domain protein 2 (PHD2) and ShPHD2 show that hypoxic expression of SDC4 mRNA and protein is regulated by PHD2 through controlling hypoxia-inducible factor 1α (HIF-1α) levels. Although overexpression of HIF-1α significantly increased SDC4 protein levels, stable suppression of HIF-1α and HIF-1β decreased SDC4 expression by 50% in human NP cells. Finally, suppression of SDC4 expression, as well as HS function, resulted in an ∼2-fold increase in sex-determining region Y (SRY)-box 9 (Sox9) mRNA, and protein (P<0.05) and simultaneous increase in Sox9 transcriptional activity and target gene expression. Taken together, our findings suggest that in healthy discs, SDC4, through its HS side chains, contributes to maintenance of the hypoxic tissue niche by controlling baseline expression of Sox9.

Original languageEnglish
Pages (from-to)2455-2465
Number of pages11
JournalFASEB Journal
Volume28
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Syndecan-4
Prolyl Hydroxylases
Hypoxia-Inducible Factor 1
Intervertebral Disc Degeneration
Heparitin Sulfate
Response Elements
SOX Transcription Factors
Messenger RNA
Proteins
Heparan Sulfate Proteoglycans
Intervertebral Disc
Back Pain
Chronic Pain
Transfection
Plasmids
Maintenance
Gene Expression
Gene expression
Mutation
Hypoxia

Keywords

  • Cartilage
  • Hypoxia
  • Intervertebral disc

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Fujita, N., Hirose, Y., Tran, C. M., Chiba, K., Miyamoto, T., Toyama, Y., ... Risbud, M. V. (2014). HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB Journal, 28(6), 2455-2465. https://doi.org/10.1096/fj.13-243741

HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. / Fujita, Nobuyuki; Hirose, Yuichiro; Tran, Cassie M.; Chiba, Kazuhiro; Miyamoto, Takeshi; Toyama, Yoshiaki; Shapiro, Irving M.; Risbud, Makarand V.

In: FASEB Journal, Vol. 28, No. 6, 2014, p. 2455-2465.

Research output: Contribution to journalArticle

Fujita, N, Hirose, Y, Tran, CM, Chiba, K, Miyamoto, T, Toyama, Y, Shapiro, IM & Risbud, MV 2014, 'HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells', FASEB Journal, vol. 28, no. 6, pp. 2455-2465. https://doi.org/10.1096/fj.13-243741
Fujita, Nobuyuki ; Hirose, Yuichiro ; Tran, Cassie M. ; Chiba, Kazuhiro ; Miyamoto, Takeshi ; Toyama, Yoshiaki ; Shapiro, Irving M. ; Risbud, Makarand V. / HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. In: FASEB Journal. 2014 ; Vol. 28, No. 6. pp. 2455-2465.
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