title: Follistatin-like 1 promotes osteoclast formation via RANKL-mediated NF-κB activation and M-CSF-induced precursor proliferation.
abstract: Follistatin-like 1 (FSTL1) functions as a pivotal modulator of inflammation and is implicated in many inflammatory diseases such as rheumatoid arthritis. Here, we report that FSTL1 is strongly upregulated and secreted during osteoclast differentiation of bone marrow-derived macrophages (BMMs) and that FSTL1 positively regulates osteoclast formation induced by RANKL and M-CSF. The overexpression of FSTL1 or treatment with recombinant FSTL1 (rFSTL1) in BMMs enhances the formation of multinuclear osteoclasts and the induction of c-Fos and NFATc1, transcription factors important for osteoclastogenesis. Conversely, knockdown of FSTL1 using a small hairpin RNA suppresses osteoclast formation and the expression of these transcription factors. While FSTL1 does not affect RANKL-stimulated activation of p38 MAPK, phosphorylation of IκBα, JNK, and ERK were increased by overexpression or addition of rFSTL1. Furthermore, rFSTL1 increased RANKL-induced NF-κB transcriptional activity in a dose-dependent manner. In addition to its role in osteoclastogenesis, FSTL1 promotes proliferation of osteoclast precursors by increasing M-CSF-induced ERK activation, which in turn leads to accelerated osteoclast formation. Together, our findings demonstrate that FSTL1 is a secreted osteoclastogenic factor that plays a critical role in osteoclast formation via the NF-κB and MAPKs signaling pathways.
authors.affiliation: Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea; Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea. Electronic address: biohjk@knu.ac.kr.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
authors.forename: Woo Youl
authors.initials: WY
authors.lastname: Kang
authors.affiliation: Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
authors.forename: Sook Jin
authors.initials: SJ
authors.lastname: Seong
authors.affiliation: Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea. Electronic address: yry@knu.ac.kr.
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D038702:Follistatin-Related Proteins / Q000378:metabolism* / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D038702:Follistatin-Related Proteins; D016328:NF-kappa B; D053245:RANK Ligand; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases
keywords: FSTL1; M-CSF; NF-κB; Osteoclast; RANKL