Department of Orthopaedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
Department of Orthopaedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Department of Orthopedics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
Lab Invest. 2023 May;103(5):100067. doi: 10.1016/j.labinv.2023.100067. Epub 2023 Jan 24.
Increased bone resorption caused by excessive number or activity of osteoclasts is the main cause of osteoporosis. Osteoclasts are multinucleated cells that are formed by the fusion of precursor cells. Although osteoclasts are primarily characterized by bone resorption, our understanding of the mechanisms that regulate the formation and function of osteoclasts is poor. Here we showed that the expression level of Rab interacting lysosomal protein (RILP) was strongly induced by receptor activator of NF-κB ligand in mouse bone marrow macrophages. Inhibition of RILP expression induced a drastic decrease in the number, size, F-actin ring formation of osteoclasts, and the expression level of osteoclast-related genes. Functionally, inhibition of RILP reduced the migration of preosteoclasts through PI3K-Akt signaling and suppressed bone resorption by inhibiting the secretion of lysosome cathepsin K. Treatments with siRNA-RILP attenuated pathologic bone loss in disease models induced by lipopolysaccharide. Thus, this work indicates that RILP plays an important role in the formation and bone resorption function of osteoclasts and may have a therapeutic potential to treat bone diseases caused by excessive or hyperactive osteoclasts.
破骨细胞数量或活性的增加是骨质疏松症的主要原因，而破骨细胞是导致骨吸收的主要细胞。破骨细胞是由前体细胞融合而成的多核细胞。尽管破骨细胞的主要特征是骨吸收，但我们对调节破骨细胞形成和功能的机制知之甚少。在这里，我们发现 Rab 相互作用的溶酶体蛋白（RILP）的表达水平在 NF-κB 配体受体激活剂诱导的小鼠骨髓巨噬细胞中被强烈诱导。抑制 RILP 的表达会导致破骨细胞的数量、大小、F-肌动蛋白环形成以及破骨细胞相关基因的表达水平急剧下降。在功能上，抑制 RILP 通过 PI3K-Akt 信号通路抑制破骨前体细胞的迁移，并通过抑制溶酶体组织蛋白酶 K 的分泌来抑制骨吸收。用 siRNA-RILP 处理可减轻脂多糖诱导的疾病模型中的病理性骨丢失。因此，这项工作表明 RILP 在破骨细胞的形成和骨吸收功能中发挥重要作用，可能具有治疗由破骨细胞过度或过度活跃引起的骨病的潜力。
