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Flrt2 is involved in fine-tuning of osteoclast multinucleation
Jumpei Shirakawa1, Noriko Takegahara1, Hyunsoo Kim1, Seoung Hoon Lee1,2, Kohji Sato3, Satoru Yamagishi3, YONGWON CHOI1,*
1Pathology and Laboratory Medicine, University of Pennsylvania,
2Oral Microbiology and Immunology, College of Dentistry, Wonkwang University,
3Organ and Tissue Anatomy, Hamamatsu University School of Medicine
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-リB 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.
Abstract, Accepted Manuscript(in press) [Submitted on April 24, 2019, Accepted on June 15, 2019]
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