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Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone
Flor M Pérez-Campo1, Ana Santurtún2, Carmen García-Ibarbia3
1Faculty of Medicine Department of Molecular Biology, University of Cantabria, Santander, Spain.
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.
Insights
Osteoporosis treatments target sclerostin (SOST). This study shows transcription factors OSX and RUNX2 activate SOST expression in human bone cells, revealing a new regulatory mechanism for bone homeostasis.
Area of Science:
- Molecular biology
- Genetics
- Bone biology
Background:
- Sclerostin (SOST) inhibits the Wnt pathway, crucial for bone homeostasis.
- Blocking sclerostin is a therapeutic strategy for osteoporosis.
- RUNX2 and OSX are key bone-specific transcription factors.
Purpose of the Study:
- To investigate the interaction of OSX and RUNX2 with the human SOST promoter.
- To determine if OSX and RUNX2 co-regulate SOST expression in human cells.
- To explore the relationship between SOST, OSX, and RUNX2 in human bone.
Main Methods:
- Analysis of the human SOST promoter for transcription factor binding sites.
- In vitro experiments to assess the activation of SOST expression by OSX and RUNX2.
- Correlation analysis of SOST, OSX, and RUNX2 expression levels in human bone samples.
- Confirmation of known associations between SOST/RUNX2 polymorphisms and bone mineral density.
Main Results:
- SP-protein family and AML1 consensus binding sequences were identified in the human SOST promoter.
- OSX and RUNX2 bind to a specific region of the SOST promoter near the transcription start site.
- OSX and RUNX2 co-ordinately activate SOST expression in vitro.
- SOST expression levels positively correlate with OSX/RUNX2 expression levels in human bone.
- Previous findings on SOST/RUNX2 polymorphisms and bone mineral density were confirmed.
Conclusions:
- OSX and RUNX2 are identified as key regulators of human SOST expression.
- This co-ordinated regulation by OSX and RUNX2 provides new insights into Wnt pathway modulation in bone.
- Understanding this regulatory mechanism could inform future anti-osteoporotic therapies targeting sclerostin.
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