title: F4/80 inhibits osteoclast differentiation via downregulation of nuclear factor of activated T cells, cytoplasmic 1.
abstract: Osteoclastogenesis is an essential process in bone metabolism, which can be induced by RANKL stimulation. The F4/80 glycoprotein is a member of the EGF-transmembrane 7 (TM7) family and has been established as a specific cell-surface marker for murine macrophages. This study aimed to identify the role of F4/80 in osteoclastogenesis. Using mouse bone marrow-derived macrophages (BMMs), we observed that the mRNA level of F4/80 was dramatically reduced as these cells differentiated into osteoclasts. Furthermore, osteoclastogenesis was decreased in F4/80highBMMs compared to F4/80-/lowBMMs. The inhibitory effect of F4/80 was associated with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). Ectopic overexpression of a constitutively active form of NFATc1 rescued the anti-osteoclastogenic effect of F4/80 completely, suggesting that the anti-osteoclastogenic effect of F4/80 was mainly due to reduction in NFATc1 expression. As an underlying mechanism, we demonstrated that the presence of F4/80 abrogated the effect of RANKL on the phosphorylation of CREB and activated the expression of IFN-β, which are restored by cyclic AMP. Collectively, our results demonstrate that the presence of F4/80 suppresses RANKL-induced osteoclastogenesis by impairing the expression of NFATc1 via CREB and IFN-β. Therefore, F4/80 may hold therapeutic potential for bone destructive diseases.
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Sim
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.
authors.forename: Ting
authors.initials: T
authors.lastname: Zheng
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea. myim@sookmyung.ac.kr.
authors.forename: Mijung
authors.initials: M
authors.lastname: Yim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*
chemical_list: D006023:Glycoproteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse
keywords: Bone loss; F4/80; NFATc1; Osteoclast; RANKL