Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease

Jumpei Teramachi, Yuko Hiruma, Seiichi Ishizuka, Hisako Ishizuka, Jacques P. Brown, Laëtitia Michou, Huiling Cao, Deborah L. Galson, Mark A. Subler, Hua Zhou, David W. Dempster, Jolene J. Windle, G. David Roodman, Noriyoshi Kurihara

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 know as calcitriol). The increased 1,25-(OH)2D3 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-(OH)2D 3'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 antisense construct decreased OCL formation and OCL precursors' sensitivity 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 receptor activator of NF-κB 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-(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. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by 1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD.

Original languageEnglish
Pages (from-to)1489-1500
Number of pages12
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume28
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

T Cell Transcription Factor 1
Activating Transcription Factors
Osteoclasts
Vitamin D
Hypersensitivity
Calcitriol
Peptides
Anti-Idiotypic Antibodies
Vitamin D Response Element
Transcription Factor TFIID
Osteitis Deformans
Peptide Initiation Factors
Calcitriol Receptors
Chromatin Immunoprecipitation
Mixed Function Oxygenases
Immunoprecipitation

Keywords

  • ATF7
  • OSTEOCLASTS
  • PAGET'S DISEASE
  • TAF12
  • VITAMIN D

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease. / Teramachi, Jumpei; Hiruma, Yuko; Ishizuka, Seiichi; Ishizuka, Hisako; Brown, Jacques P.; Michou, Laëtitia; Cao, Huiling; Galson, Deborah L.; Subler, Mark A.; Zhou, Hua; Dempster, David W.; Windle, Jolene J.; Roodman, G. David; Kurihara, Noriyoshi.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 28, No. 6, 06.2013, p. 1489-1500.

Research output: Contribution to journalArticle

Teramachi, Jumpei ; Hiruma, Yuko ; Ishizuka, Seiichi ; Ishizuka, Hisako ; Brown, Jacques P. ; Michou, Laëtitia ; Cao, Huiling ; Galson, Deborah L. ; Subler, Mark A. ; Zhou, Hua ; Dempster, David W. ; Windle, Jolene J. ; Roodman, G. David ; Kurihara, Noriyoshi. / Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 ; Vol. 28, No. 6. pp. 1489-1500.
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T1 - Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease

AU - Teramachi, Jumpei

AU - Hiruma, Yuko

AU - Ishizuka, Seiichi

AU - Ishizuka, Hisako

AU - Brown, Jacques P.

AU - Michou, Laëtitia

AU - Cao, Huiling

AU - Galson, Deborah L.

AU - Subler, Mark A.

AU - Zhou, Hua

AU - Dempster, David W.

AU - Windle, Jolene J.

AU - Roodman, G. David

AU - Kurihara, Noriyoshi

PY - 2013/6

Y1 - 2013/6

N2 - 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 know as calcitriol). The increased 1,25-(OH)2D3 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-(OH)2D 3'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 antisense construct decreased OCL formation and OCL precursors' sensitivity 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 receptor activator of NF-κB 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-(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. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by 1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD.

AB - 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 know as calcitriol). The increased 1,25-(OH)2D3 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-(OH)2D 3'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 antisense construct decreased OCL formation and OCL precursors' sensitivity 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 receptor activator of NF-κB 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-(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. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by 1,25-(OH)2D3, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)2D3 in PD.

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KW - OSTEOCLASTS

KW - PAGET'S DISEASE

KW - TAF12

KW - VITAMIN D

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