Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

成熟的破骨细胞通过分泌性溶酶体通过褶皱边界胞吐活性蛋白酶来降解骨基质。然而，破骨细胞中溶酶体运输和分泌的分子机制仍然很大程度上未知。在这里，我们通过基因芯片分析表明，含有 RUN 和 FYVE 结构域的蛋白 4 (RUFY4) 在破骨细胞生成过程中强烈上调。缺乏Rufy4的小鼠表现出高小梁骨量表型，体内破骨细胞功能异常。此外，删除Rufy4并不影响破骨细胞的分化，但由于次级溶酶体的酸性成熟、它们向膜的运输以及它们将组织蛋白酶K分泌到细胞外空间的破坏而抑制骨吸收活性。从机制上讲，RUFY4 通过充当晚期内体上的 Rab7 和初级溶酶体上的 LAMP2 之间的衔接蛋白来促进晚期内体-溶酶体融合。因此，Rufy4缺陷小鼠受到高度保护，免受脂多糖和卵巢切除引起的骨质流失。因此，RUFY4通过介导内溶酶体运输而成为破骨细胞活性的新调节剂，并有可能成为治疗骨质疏松症等骨质流失疾病的特定靶点。