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Regulation and Function of FOXC1 in Osteoblasts.
Sarocha Suthon1, Jianjian Lin1, Rachel S Perkins1
1Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Journal of Developmental Biology
|September 27, 2023
Summary
Estrogen receptor alpha (ERα) signaling regulates bone density by controlling FOXC1 expression. GATA4 and FOXC1 transcription factors interact to influence osteoblast differentiation and bone formation.
Area of Science:
- Endocrinology
- Molecular Biology
- Bone Biology
Background:
- Estrogens are crucial for maintaining bone mineral density.
- Menopause-induced estrogen decline leads to reduced bone quality and increased fracture risk.
- Estrogen receptor alpha (ERα) binding sites are enriched near the FOXC1 gene in osteoblasts.
Purpose of the Study:
- To investigate the role of ERα, FOXC1, and GATA4 in osteoblast differentiation.
- To elucidate the molecular mechanisms regulating FOXC1 expression by estrogen.
- To understand the cooperative interactions between GATA4 and FOXC1 in bone formation.
Main Methods:
- Primary mouse and human osteoblast cultures.
- Quantitative real-time PCR and Western blotting to measure gene and protein expression.
- Chromatin immunoprecipitation (ChIP-reChIP) and luciferase assays to assess protein interactions and transcriptional regulation.
- GATA4 knockdown in vitro and knockout in vivo models.
Main Results:
- 17β-estradiol (E2) treatment increased FOXC1 mRNA and protein levels in osteoblasts.
- GATA4 was recruited to enhancers near the Foxc1 gene and its knockdown/knockout decreased Foxc1 expression.
- GATA4 and FOXC1 physically interact and co-regulate osteoblast differentiation genes, including RUNX2.
- FOXC1 motifs were highly enriched in GATA4 binding sites, indicating cooperative regulation.
Conclusions:
- Estrogen signaling, through ERα, directly upregulates FOXC1 expression in osteoblasts.
- The pioneer factor GATA4 plays a critical role in mediating ERα's effect on FOXC1.
- GATA4 and FOXC1 form a regulatory complex that is essential for osteoblast differentiation and bone formation.
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