ArticleThe Journal of biological chemistry2013
Hypoxia-inducible factor (HIF)-1α and CCN2 form a regulatory circuit in hypoxic nucleus pulposus cells: CCN2 suppresses HIF-1α level and transcriptional activity.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- Review
- The notochord: development, disease and stem cell-based modelling.Development (Cambridge, England) · 2026Review
- 5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target.Clinical and translational medicine · 2025Article
- Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment.Frontiers in immunology · 2023Review
- Multifunctional regulatory protein connective tissue growth factor (CTGF): A potential therapeutic target for diverse diseases.Acta pharmaceutica Sinica. B · 2022Review
- Application of mesenchymal stem cell-derived exosomes from different sources in intervertebral disc degeneration.Frontiers in bioengineering and biotechnology · 2022Review
- The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.Nature reviews. Rheumatology · 2021Review
- Hypoxia and Hypoxia-Inducible Factor-1α Regulate Endoplasmic Reticulum Stress in Nucleus Pulposus Cells: Implications of Endoplasmic Reticulum Stress for Extracellular Matrix Secretion.The American journal of pathology · 2021Article
- Hub Genes and Key Pathways of Intervertebral Disc Degeneration: Bioinformatics Analysis and Validation.BioMed research international · 2021Article
- HIF-1Oxidative medicine and cellular longevity · 2021Article
- Nov/CCN3 Enhances Cord Blood Engraftment by Rapidly Recruiting Latent Human Stem Cell Activity.Cell stem cell · 2020Article
- Exosomes Derived from Human Urine-Derived Stem Cells Inhibit Intervertebral Disc Degeneration by Ameliorating Endoplasmic Reticulum Stress.Oxidative medicine and cellular longevity · 2020Article
- Bicarbonate Recycling by HIF-1-Dependent Carbonic Anhydrase Isoforms 9 and 12 Is Critical in Maintaining Intracellular pH and Viability of Nucleus Pulposus Cells.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2018Article
- Hypoxia-inducible factor (HIF)-1alpha knockout accelerates intervertebral disc degeneration in mice.International journal of clinical and experimental pathology · 2018Article
- Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy, development and function.Cell and tissue research · 2017Review
- IL-1β increases asporin expression via the NF-κB p65 pathway in nucleus pulposus cells during intervertebral disc degeneration.Scientific reports · 2017Article
- Osteoblast Hypoxia-Inducible Factor-1α Pathway Activation Restrains OsteoclastogenesisFrontiers in immunology · 2017Article
- Ageing in the musculoskeletal system.Acta orthopaedica · 2016Review
- Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling.Autophagy · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The objective of the study was to investigate if hypoxia-inducible factor (HIF)-1α and connective tissue growth factor (CCN2) form a regulatory network in hypoxic nucleus pulposus (NP) cells. A decrease in CCN2 expression and proximal promoter activity was observed in NP cells after hypoxic culture. Analysis of both human and mouse CCN2 promoters using the JASPAR core database revealed the presence of putative hypoxia response elements. Transfection experiments showed that both promoter activities and CCN2 expression decreases in hypoxia in a HIF-1α-dependent fashion. Interestingly, deletion analysis and mutation of the hypoxia responsive elements individually or in combination resulted in no change in promoter activity in response to hypoxia or in response to HIF-1α, suggesting an indirect mode of regulation. Notably, silencing of endogenous CCN2 increased HIF-1α levels and its target gene expression, suggesting a role for CCN2 in controlling basal HIF-1α levels. On the other hand, treatment of cells with rCCN2 resulted in a decrease in the ability of HIF-1α transactivating domain to recruit co-activators and diminished target gene expression. Last, knockdown of CCN2 in NP cells results in a significant decrease in GAG synthesis and expression of AGGRECAN and COLLAGEN II. Immunohistochemical staining of intervertebral discs of Ccn2 null embryos shows a decrease in aggrecan. These findings reveal a negative feedback loop between CCN2 and HIF-1α in NP cells and demonstrate a role for CCN2 in maintaining matrix homeostasis in this tissue.
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