ATF3 controls proliferation of osteoclast precursor and bone remodeling

• Published in: Scientific reports Vol. 6; no. 1; p. 30918
• Main Authors: Fukasawa, Kazuya, Park, Gyujin, Iezaki, Takashi, Horie, Tetsuhiro, Kanayama, Takashi, Ozaki, Kakeru, Onishi, Yuki, Takahata, Yoshifumi, Yoneda, Yukio, Takarada, Takeshi, Kitajima, Shigetaka, Vacher, Jean, Hinoi, Eiichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-08-2016; Nature Publishing Group
• Subjects: 13/109; 631/250/808; 631/337/572/2102; 64/60; Activating transcription factor 3; Activating Transcription Factor 3 - physiology; Activator protein 1; Animals; Bone diseases; Bone loss; Bone marrow; Bone Marrow Cells - metabolism; Bone Remodeling; Bone resorption; Bone Resorption - etiology; Bone Resorption - metabolism; Bone Resorption - pathology; Bone Resorption - prevention & control; Bone turnover; Cell Differentiation; Cell growth; Cell Proliferation; Clonal deletion; Cyclin D1; Gene expression; Gene Expression Regulation; Gene regulation; Homeostasis; Humanities and Social Sciences; Macrophages; Macrophages - cytology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Osteoblasts; Osteoclastogenesis; Osteoclasts; Osteoclasts - cytology; Osteoclasts - metabolism; Osteoprogenitor cells; RANK Ligand - adverse effects; Rodents; Science; TRANCE protein; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep30918

Bone homeostasis is maintained by the sophisticated coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-κB (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition. RANKL-dependent osteoclastogenesis was impaired
in vitro
in ATF3-deleted bone marrow macrophages (BMM). Mechanistically, the deficiency of ATF3 impaired the RANKL-induced transient increase in cell proliferation of osteoclast precursors in bone marrow
in vivo
as well as of BMM
in vitro
. Moreover, ATF3 regulated cyclin D1 mRNA expression though modulating activator protein-1-dependent transcription in the osteoclast precursor and the introduction of cyclin D1 significantly rescued the impairment of osteoclastogenesis in ATF3-deleted BMM. Therefore, these findings suggest that ATF3 could have a pivotal role in osteoclastogenesis and bone homeostasis though modulating cell proliferation under pathological conditions, thereby providing a target for bone diseases.