BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Flrt2 is involved in fine-tuning of osteoclast multinucleation

  • Shirakawa, Jumpei (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Takegahara, Noriko (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Kim, Hyunsoo (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Lee, Seoung Hoon (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine) ;
  • Sato, Kohji (Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine) ;
  • Yamagishi, Satoru (Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine) ;
  • Choi, Yongwon (Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine)
  • Received : 2019.04.24
  • Accepted : 2019.06.15
  • Published : 2019.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Osteoclasts are multinucleated giant cells derived from myeloid progenitors. Excessive bone resorption by osteoclasts can result in serious clinical outcomes for which better treatment options are needed. Here, we identified fibronectin leucine-rich transmembrane protein 2 (Flrt2), a ligand of the Unc5 receptor family for neurons, as a novel target associated with the late/maturation stage of osteoclast differentiation. Flrt2 expression is induced by stimulation with receptor activator of nuclear factor-kB ligand (RANKL). Flrt2 deficiency in osteoclasts results in reduced hyper-multinucleation, which could be restored by RNAi-mediated knockdown of Unc5b. Treatment with Netrin1, another ligand of Unc5b which negatively controls osteoclast multinucleation through down regulation of RANKL-induced Rac1 activation, showed no inhibitory effects on Flrt2-deficient cells. In addition, RANKL-induced Rac1 activation was attenuated in Flrt2-deficient cells. Taken together, these results suggest that Flrt2 regulates osteoclast multinucleation by interfering with Netrin 1-Unc5b interaction and may be a suitable therapeutic target for diseases associated with bone remodeling.

Keywords

References

  1. Teitelbaum SL and Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638-649 https://doi.org/10.1038/nrg1122
  2. Walsh MC, Kim N, Kadono Y et al (2006) Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol 24, 33-63 https://doi.org/10.1146/annurev.immunol.24.021605.090646
  3. Nakashima T, Hayashi M, Fukunaga T et al (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17, 1231-1234 https://doi.org/10.1038/nm.2452
  4. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC and O'Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17, 1235-1241 https://doi.org/10.1038/nm.2448
  5. Moutsopoulos NM, Konkel J, Sarmadi M et al (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6, 229ra240
  6. Souza PP and Lerner UH (2013) The role of cytokines in inflammatory bone loss. Immunol Invest 42, 555-622 https://doi.org/10.3109/08820139.2013.822766
  7. Miyazaki T, Tokimura F and Tanaka S (2014) A review of denosumab for the treatment of osteoporosis. Patient Prefer Adherence 8, 463-471 https://doi.org/10.2147/PPA.S46192
  8. Kim H, Walsh MC, Takegahara N et al (2017) The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. Sci Rep 7, 196 https://doi.org/10.1038/s41598-017-00139-2
  9. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289, 1504-1508 https://doi.org/10.1126/science.289.5484.1504
  10. Yagi M, Miyamoto T, Sawatani Y et al (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202, 345-351 https://doi.org/10.1084/jem.20050645
  11. Binder NB, Niederreiter B, Hoffmann O et al (2009) Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis. Nat Med 15, 417-424 https://doi.org/10.1038/nm.1945
  12. Lacy SE, Bonnemann CG, Buzney EA and Kunkel LM (1999) Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins. Genomics 62, 417-426 https://doi.org/10.1006/geno.1999.6033
  13. Karaulanov EE, Bottcher RT and Niehrs C (2006) A role for fibronectin-leucine-rich transmembrane cell-surface proteins in homotypic cell adhesion. EMBO Rep 7, 283-290 https://doi.org/10.1038/sj.embor.7400614
  14. Egea J, Erlacher C, Montanez E et al (2008) Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation. Genes Dev 22, 3349-3362 https://doi.org/10.1101/gad.486708
  15. Leyva-Diaz E, del Toro D, Menal MJ et al (2014) FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons. Curr Biol 24, 494-508 https://doi.org/10.1016/j.cub.2014.01.042
  16. Maretto S, Muller PS, Aricescu AR, Cho KW, Bikoff EK and Robertson EJ (2008) Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3. Dev Biol 318, 184-193 https://doi.org/10.1016/j.ydbio.2008.03.021
  17. Muller PS, Schulz R, Maretto S et al (2011) The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis. Development 138, 1297-1308 https://doi.org/10.1242/dev.059386
  18. O'Sullivan ML, de Wit J, Savas JN et al (2012) FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73, 903-910 https://doi.org/10.1016/j.neuron.2012.01.018
  19. Yamagishi S, Hampel F, Hata K et al (2011) FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J 30, 2920-2933 https://doi.org/10.1038/emboj.2011.189
  20. Tai-Nagara I, Yoshikawa Y, Numata N et al (2017) Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling. Development 144, 2392-2401 https://doi.org/10.1242/dev.149757
  21. Seiradake E, del Toro D, Nagel D et al (2014) FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron 84, 370-385 https://doi.org/10.1016/j.neuron.2014.10.008
  22. Jackson VA, del Toro D, Carrasquero M et al (2015) Structural basis of latrophilin-FLRT interaction. Structure 23, 774-781 https://doi.org/10.1016/j.str.2015.01.013
  23. Maruyama K, Kawasaki T, Hamaguchi M et al (2016) Bone-protective functions of netrin 1 Protein. J Biol Chem 291, 23854-23868 https://doi.org/10.1074/jbc.M116.738518
  24. Seiradake E, Jones EY and Klein R (2016) Structural Perspectives on Axon Guidance. Annu Rev Cell Dev Biol 32, 577-608 https://doi.org/10.1146/annurev-cellbio-111315-125008
  25. Zhu S, Zhu J, Zhen G et al (2019) Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest 129, 1076-1093 https://doi.org/10.1172/JCI121561
  26. Takegahara N, Kim H, Mizuno H et al (2016) Involvement of receptor activator of nuclear factor-kappaB ligand (RANKL)-induced incomplete cytokinesis in the polyploidization of osteoclasts. J Biol Chem 291, 3439-3454 https://doi.org/10.1074/jbc.M115.677427
  27. Paiva KBS and Granjeiro JM (2017) matrix metalloproteinases in bone resorption, remodeling, and repair. Prog Mol Biol Transl Sci 148, 203-303 https://doi.org/10.1016/bs.pmbts.2017.05.001