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Paget's disease-a VDR coactivator disease?
Noriyoshi Kurihara1, Seiichi Ishizuka, Anne Demulder
1Department of Medicine/Hematology, University of Pittsburgh, Kaufmann Medical Building, Suite 601, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
Summary
Paget's disease involves abnormal bone remodeling. Researchers found that cells forming bone-resorbing cells (osteoclasts) in Paget's patients are overly sensitive to Vitamin D due to increased coactivator proteins.
Area of Science:
- Endocrinology
- Bone Biology
- Genetics
Background:
- Paget's disease is characterized by exaggerated bone remodeling, marked by heightened osteoclastic bone resorption and excessive bone formation.
- Osteoclast precursors in Paget's disease exhibit hyper-responsiveness to 1,25-(OH)(2)D(3), forming osteoclasts at physiological concentrations.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the enhanced sensitivity of osteoclast precursors to 1,25-(OH)(2)D(3) in Paget's disease.
- To identify factors contributing to the increased osteoclast formation observed in Paget's disease.
Main Methods:
- Utilized GST-VDR chimeric protein pull-down assays to analyze protein interactions.
- Quantified levels of Vitamin D receptor (VDR), TAF(II)-17, CPB300, and DRIP205 in osteoclast precursors from Paget's patients and normal individuals.
Main Results:
- Increased expression of TAF(II)-17, a component of the TAF(II)-D transcription complex, was observed in Paget's disease osteoclast precursors.
- TAF(II)-17 enhances VDR-mediated gene transcription, facilitating transcription complex formation at low 1,25-(OH)(2)D(3) concentrations.
- Coactivators of VDR, including CPB300 and DRIP205, were also found to be elevated in Paget's disease osteoclast precursors.
Conclusions:
- The enhanced sensitivity of osteoclast precursors to 1,25-(OH)(2)D(3) in Paget's disease is attributed to increased expression of VDR coactivators.
- Elevated expression of VDR coactivators may contribute to the pathophysiology of excessive osteoclast formation in Paget's disease.