The Role of the Vitamin D Receptor in Paget's Disease

Objectives: Paget's Disease is the most exaggerated example of bone remodeling with increased osteoclastic bone resorption followed by abundant bone formation that is of poor quality. The primary cell responsible for Paget's disease is the osteoclast (OCL). OCL in Paget's disease are increased in number and size and contain measles virus like nucleocapsid inclusions and mRNA, as well as have an increased bone resorbing capacity. Methods: We demonstrated that transfection of the measles virus nucleocapsid gene (MVNP) into normal OCL precursors, results in formation of OCL that have many of the characteristics of Pagetic OCL, including increased responsivity to 1,25-(OH)₂D₃. Results: We have previously shown that Pagetic OCL precursors can form OCL at physiologic concentrations of 1,25-(OH)₂D₃, which does not occur with normals. VDR numbers and the Kd for VDR are similar between Pagetic OCL precursors and normals. These data suggest that expression of the MVNP gene in OCL precursors in patients with Paget's disease increases expression of a coactivator of VDR. To test this hypothesis, lysates from normal OCL precursors, Pagetic OCL precursors and osteoclast precursors transfected with MVNP, were incubated with a GST-VDR construct. A 17Kda protein was identified, which was TAF_II-17. TAF_II-17 is a member of the TAFIID transcription complex. Transfection of TAF_II-17 into NIH-3T3 cells made them hyperresponsive to 1,25-(OH)₂D₃. In contrast, TAF_II-17 did not enhance their sensitivity to retinoic acid. Conclusions: Transfection of an antisense construct to TAF_II-17 into Pagetic OCL precursors significantly decreased OCL formation but had no effect on normal OCL formation. Also, other VDR coactivators, SRC-1, SRC-3, and DRIP-205 are increased. We have shown that an antagonist to VDR, (23S)-25-dehydro-1a-(OH)₃-26,23-lactone inhibited Pagetic OCL formation. These data suggest that a potent antagonist to VDR can inhibit OCL formation in patients with Paget's disease, and may be a useful therapy for these patients.