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AB0069 Follistatin-like 1 Promotes Osteoclast Differentiation via RANKL-Mediated Activation of NF-κB and MAPK Signaling Pathways
  1. H.-J. Kim,
  2. H.-J. Yoon,
  3. W.Y. Kang,
  4. S.J. Seong,
  5. Y.-R. Yoon
  1. Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, Kyungpook National University, Daegu, Korea, Republic Of

Abstract

Background Follistatin-like 1 (FSTL1) functions as a pivotal modulator of inflammation and is implicated in many inflammatory diseases such as rheumatoid arthritis, yet its role in osteoclast development is currently unknown.

Objectives The aim of this study was to investigate the role of FSTL1 in osteoclast development mediated by M-CSF and RANKL.

Methods Osteoclastogenesis was assessed using mouse primary bone marrow-derived macrophages. The mRNA expression was analyzed by real-time or RT-PCR. RANKL or M-CSF signaling was assessed by immunoblotting and NF-κB transcriptional activity by luciferase reporter assay. Apoptosis assay was performed by cell death ELISA and cell proliferation using BrdU ELISA system.

Results We show that FSTL1 expression is strongly upregulated during osteoclast differentiation of bone marrow-derived macrophages (BMMs) and FSTL1 positively regulates receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The overexpression of FSTL1 or the treatment of recombinant FSTL1 (rFSTL1) in BMMs enhances the formation of multinuclear osteoclasts and the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), transcription factors important for osteoclastogenesis. Conversely, knockdown of FSTL1 using a small hairpin RNA suppresses RANKL-mediated osteoclast formation and the expression of these transcription factors. While FSTL1 does not affect the RANKL-stimulated activation of p38 MAPK, the phosphorylation of IκBa, JNK, and ERK was increased by overexpression or addition of rFSTL1. Furthermore, rFSTL1 accelerated RANKL-induced NF-κB transcriptional activity in a dose-dependent manner.

Conclusions Our study demonstrates that FSTL1 promotes osteoclast differentiation by stimulating NF-κB and MAPK activation in response to RANKL. Thus, we identify FSTL1 as a pro-osteoclastogenic factor that plays an important role in RANKL-induced osteoclast differentiation.

  1. Teitelbaum, S. L. and F. P. Ross. 2003. Genetic regulation of osteoclast development and function. Nat Rev Genet 4: 638–649.

  2. Chaly, Y. et al. 2012. FSTL1 promotes arthritis in mice by enhancing inflammatory cytokine/chemokine expression. Arthritis and rheumatism 64(4):1082–1088.

  3. Miyamae, T. et al. 2006. Follistatin-like protein-1 is a novel proinflammatory molecule. J Immunol 177(7):4758–4762.

Acknowledgement This research was supported by the Basic Science Research Program of the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science, and Technology (NRF-2015R1D1A1A01056666) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Korea (HI15C0001, HI14C2750).

Disclosure of Interest None declared

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