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

Osteoclast OCL precursors from 70 of Pagets disease PD patients express measles virus nucleocapsid protein MVNP and are hypersensitive to 1,25-dihydroxyvitamin D3 1,25-OH2D3 also known as calcitriol. The increased 1,25-OH2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 TAF12, a coactivator of the vitamin D receptor VDR, which 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-OH2D3s 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 antisense construct decreased OCL formation and OCL precursors sensitivity to 1,25-OH2D3 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-OH2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF- B ligand RANKL hypersensitivity and hypermultinucleation. 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-OH2D3. 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.