Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan 54538, Korea.
BMB Rep. 2019 Aug;52(8):514-519. doi: 10.5483/BMBRep.2019.52.8.116.
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. [BMB Reports 2019; 52(8): 514-519].
破骨细胞是来源于髓样祖细胞的多核巨细胞。破骨细胞的过度骨吸收会导致严重的临床后果，因此需要更好的治疗选择。在这里，我们鉴定了纤维连接蛋白富含亮氨酸跨膜蛋白 2（Flrt2），一种神经元的 Unc5 受体家族的配体，作为与破骨细胞分化的晚期/成熟阶段相关的新的靶标。Flrt2 的表达受核因子-kB 受体激活剂（RANKL）的刺激诱导。破骨细胞中的 Flrt2 缺失导致超多核化减少，这可以通过 RNAi 介导的 Unc5b 的敲低来恢复。另一种配体 Netrin1 处理，通过下调 RANKL 诱导的 Rac1 激活来负调控破骨细胞多核化，对 Flrt2 缺陷细胞没有抑制作用。此外，Flrt2 缺陷细胞中 RANKL 诱导的 Rac1 激活减弱。综上所述，这些结果表明 Flrt2 通过干扰 Netrin 1-Unc5b 相互作用来调节破骨细胞多核化，可能是与骨重塑相关疾病的合适治疗靶点。[BMB 报告 2019；52(8): 514-519]。
