ArticlePloS one2013
HIF-1α inhibits Wnt signaling pathway by activating Sost expression in osteoblasts.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Osteoporosis in COPD patients: Risk factors and pulmonary rehabilitation.The clinical respiratory journal · 2022Pooled it
- Sclerostin in Vascular Calcification: Hypoxia-Driven Regulation and Therapeutic Modulation by Natural Products.Current atherosclerosis reports · 2026Review
- Research Progress on Signaling Pathways in Breast Cancer Bone Metastasis.Oncology research · 2026Review
- Osteosarcopenia: epidemiology, molecular mechanisms, and management.Frontiers in endocrinology · 2025Review
- Association between endometrial cancer and subsequent risk of fracture: a national cohort study.Frontiers in endocrinology · 2025Observational
- Physiological and molecular mechanisms of tolerance to hypoxia and oxygen deficiency resistance markers.Frontiers in molecular biosciences · 2025Review
- Activation of Wnt signaling in human fracture callus and nonunion tissues.Bone reports · 2024Article
- Hypoxia inducible factor-1α related mechanism and TCM intervention in process of early fracture healing.Chinese herbal medicines · 2024Review
- SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption.Scientific reports · 2023Article
- Low Lung Function Is Associated with Low Baseline Calcaneus Ultrasound T-Score but a Slow Decline in T-Score in a Taiwanese Follow-Up Population with No History of Smoking, Bronchitis, Emphysema, or Asthma.Journal of personalized medicine · 2023Article
- Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair.International journal of molecular sciences · 2022Review
- The Cellular Choreography of Osteoblast Angiotropism in Bone Development and Homeostasis.International journal of molecular sciences · 2021Review
- Effects of normobaric cyclic hypoxia exposure on mesenchymal stem-cell differentiation-pilot study on bone parameters in elderly.World journal of stem cells · 2020Article
- Review
- Proangiogenic Hypoxia-Mimicking Agents Attenuate Osteogenic Potential of Adipose Stem/Stromal Cells.Tissue engineering and regenerative medicine · 2020Article
- Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways.Nature communications · 2020Article
- COPD as an independent risk factor for osteoporosis and fractures.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2020Article
- The Effects of Sclerostin on the Immune System.Current osteoporosis reports · 2020Review
- Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis.International journal of molecular sciences · 2019Review
- Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies.Current osteoporosis reports · 2019Review
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Authors and funding
8 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The nature of the cellular and molecular mechanisms for the transition of avascular cartilage replacement with bone during endochondral ossification remains poorly understood. One of the driving forces is hypoxia. As a master regulator of hypoxia, hypoxia-inducible factor-1α (HIF-1α) has been reported to couple angiogenesis to osteogenesis. Our recent study has demonstrated that osteoblast growth is inhibited under hypoxia and that HIF-1α cooperates with Osterix (Osx) to inhibit Wnt pathway. However, molecular mechanisms for inhibitory effects of HIF-1α on Wnt pathway are not well understood. In this study, our quantitative RT-PCR results revealed that the expression of a Wnt antagonist Sclerostin (Sost) was upregulated in osteoblasts during hypoxia while HIF-1α was upregulated. Treatment of desferrioxamine (DFO), a HIF-1α activator, led to further increase of Sost expression, suggesting that HIF-1α may activate Sost expression. The regulation of Sost gene expression by HIF-1α was then investigated. We performed loss-of-function experiments to examine Sost expression by using siRNA approach against HIF-1α, and found that the inhibition of HIF-1α by siRNA in osteoblasts led to the decrease of Sost expression. To address transcriptional regulation of Sost gene by HIF-1α, transient transfection assay was performed and showed that HIF-1α activated Sost-1 kb promoter reporter activity in a dose-dependent manner. To narrow down the minimal region of Sost promoter activated by HIF-1α, we generated a series of deletion mutants of Sost constructs. It was demonstrated that Sost-260 was the minimal region of Sost promoter for HIF-1α activation and that Sost-106 construct, which lack hypoxia response element, abolished HIF-1α-mediated Sost reporter activation. Gel shift assay showed that HIF-1 bound to the promoter sequence of Sost directly. These findings support our hypothesis that HIF-1α activates Sost expression. This study provides a novel molecular mechanism through which HIF-1α inhibits Wnt signaling in osteoblasts.
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