Role of TAF12 in the Increased VDR Activity in Paget's Disease of Bone

Abstract

Abstract : Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25- dihydroxyvitamin D3 (1,25-(OH)2D3; also known as calcitriol). The increased 1,25- (OH)2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of vitamin D receptor (VDR) mediated transcriptionTAF12 is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3's effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 anti-sense construct decreased OCL formation and the sensitivity of OCL precursors to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase TRAP-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including hypermultinucleation and receptor activator of NF- B ligand (RANKL) hypersensitivity. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti- TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)2D3. Because TAF12 directly interacts with the cyclic adenosine monophosphate dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors.