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Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

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Abstract

Sclerostin, encoded by the SOST gene, works as an inhibitor of the Wnt pathway and therefore is an important regulator of bone homeostasis. Due to its potent action as an inhibitor of bone formation, blocking sclerostin activity is the purpose of recently developed anti-osteoporotic treatments. Two bone-specific transcription factors, RUNX2 and OSX, have been shown to interact and co-ordinately regulate the expression of bone-specific genes. Although it has been recently shown that sclerostin is targeted by OSX in mice, there is currently no information of whether this is also the case in human cells. We have identified SP-protein family and AML1 consensus binding sequences at the human SOST promoter and have shown that OSX, together with RUNX2, binds to a specific region close to the transcription start site. Furthermore, we show that OSX and RUNX2 activate SOST expression in a co-ordinated manner in vitro and that SOST expression levels show a significant positive correlation with OSX/RUNX2 expression levels in human bone. We also confirmed previous results showing an association of several SOST/RUNX2 polymorphisms with bone mineral density.

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Acknowledgments

This research was supported by grants from the Spanish Ministry of Health and the Instituto de Salud Carlos III (PI12-0615), which may be cofunded by the FEDER funds from the European Union, and the Fundación Española de Investigación Osea y Metabolismo Mineral (FEIOMM). C. Sañudo is supported by IDIVAL (Instituto de Investigación Marqués de Valdecilla).

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Authors and Affiliations

  1. Faculty of Medicine Department of Molecular Biology, University of Cantabria, Santander, Spain

    Flor M. Pérez-Campo

  2. Unit of Legal Medicine, Faculty of Medicine, University of Cantabria, Santander, Spain

    Ana Santurtún & María T. Zarrabeitia

  3. Department of Internal Medicine, Hospital U. Marqués de Valdecilla-IDIVAL, University of Cantabria, Avda. Valdecilla S/N, 39008, Santander, Spain

    Carmen García-Ibarbia, Carmen Valero, Carolina Sañudo & José A. Riancho

  4. Service of Traumatology and Orthopedic Surgery, Hospital U. Marqués de Valdecilla, University of Cantabria, Santander, Spain

    María A. Pascual & Carlos Garcés

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  1. Flor M. Pérez-Campo
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  2. Ana Santurtún
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  3. Carmen García-Ibarbia
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  4. María A. Pascual
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  5. Carmen Valero
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  6. Carlos Garcés
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  7. Carolina Sañudo
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  8. María T. Zarrabeitia
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  9. José A. Riancho
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Corresponding author

Correspondence to José A. Riancho.

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Conflict of Interest

Flor M. Pérez-Campo, Ana Santurtún, Carmen García-Ibarbia, María A. Pascual, Carmen Valero, Carlos Garcés, Carolina Sañudo, María T. Zarrabeitia and José A. Riancho declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

As part of a project to determine genetic factors associated with osteoporosis, the study was approved by the IRB (Comité de Etica en Investigación Clínica de Cantabria) and participants provided informed consent.

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Pérez-Campo, F.M., Santurtún, A., García-Ibarbia, C. et al. Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone. Calcif Tissue Int 99, 302–309 (2016). https://doi.org/10.1007/s00223-016-0144-4

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