ATF3 modulates calcium signaling in osteoclast differentiation and activity by associating with c-Fos and NFATc1 proteins.
Activating transcription factor 3 (ATF3), a member of the ATF/cAMP response element-binding protein family of transcription factors, has been implicated in the regulation of cell proliferation and differentiation. However, whether ATF3 is involved in osteoclast differentiation and activity has not been well-studied. In the present study, we examined the role of ATF3 in osteoclast differentiation and function. ATF3 expression was down-regulated during RANKL-induced osteoclast differentiation. Overexpression of ATF3 in bone marrow-derived monocyte/macrophage lineage cells (BMMs) promoted osteoclast differentiation and activity and strongly induced the expression of osteoclast genes encoding nuclear factor of activated T-cells c1 (NFATc1) and tartrate-resistant acid phosphatase (TRAP) compared to that in the control group. In contrast, small interfering RNA-mediated knockdown of ATF3 prevented the formation of multinucleated osteoclasts and markedly abrogated the expression of osteoclast marker genes. Mechanistically, ATF3 synergistically enhanced c-Fos- or NFAT-mediated transcriptional activity of the NFATc1 or TRAP promoter, respectively. Furthermore, ATF3 physically interacted with c-Fos and NFATc1 and enhanced the binding affinity of c-Fos and NFATc1 to the promoters. Interestingly, ATF3 is involved in calcium signaling during osteoclastogenesis. Taken together, these results suggest that ATF3 is a new co-factor of c-Fos and NFATc1 to activate osteoclast differentiation and activity.
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; Department of Pharmacology, Seonam University Medical School, Namwon, Chonbuk 55724, Republic of Korea.
Byung-Chul
BC
Jeong
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Jung Ha
JH
Kim
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Kabsun
K
Kim
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Inyoung
I
Kim
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Semun
S
Seong
Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea. Electronic address: nacksung@jnu.ac.kr.
Nacksung
N
Kim
D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D002454:Cell Differentiation; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008813:Mice, Inbred ICR; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D051700:Activating Transcription Factor 3; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand
Activating transcription factor 3; Calcium signaling; Osteoclasts; RANKL