Kim Jung Ha, Seong Semun, Kim Kabsun, Kim Inyoung, Park Jeong Woo, Koh Jeong-Tae, Kim Nacksung
Department of Pharmacology, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
Cell Death Discov. 2025 Feb 5;11(1):48. doi: 10.1038/s41420-025-02338-7.
Multiple small GTPases play crucial roles in bone homeostasis by regulating the differentiation and function of bone cells, including osteoclasts and osteoblasts. Here, we investigated whether developmentally regulated GTP-binding protein 2 (Drg2), a subfamily of the GTPase superfamily, could affect bone mass by regulating osteoclast and osteoblast differentiation. Downregulation of Drg2 using siRNA in bone marrow-derived macrophages inhibited osteoclast differentiation and function and Rac1 activation in vitro. Comparatively, Drg2 downregulation in calvarial-derived osteoprogenitor cells enhanced osteoblast differentiation and function in vitro. Rac1 activation was also suppressed by Drg2 downregulation in osteoprogenitor cells. Both osteoclast and osteoblast differentiation regulated by Drg2 downregulation were restored by suppressing Rac1 activity. Drg2-deficient mice showed increased bone mass due to a dramatic reduction in osteoclast numbers without significantly affecting the number of osteoblasts. Furthermore, Drg2 downregulation strongly inhibited RANKL-induced bone loss in vivo. In summary, Drg2 contributes to bone homeostasis by regulating the differentiation and function of osteoclasts and osteoblasts through Rac1 activation. In particular, the effect of Drg2 on osteoclasts is strong enough to regulate bone mass in vivo; therefore, Drg2 has significant potential for use as a therapeutic target in bone loss-related diseases.
多种小GTP酶通过调节骨细胞（包括破骨细胞和成骨细胞）的分化和功能，在骨稳态中发挥关键作用。在此，我们研究了GTP酶超家族的一个亚家族——发育调控型GTP结合蛋白2（Drg2）是否能通过调节破骨细胞和成骨细胞的分化来影响骨量。在骨髓来源的巨噬细胞中使用小干扰RNA下调Drg2可抑制体外破骨细胞的分化、功能及Rac1激活。相比之下，在颅骨来源的骨祖细胞中下调Drg2可增强体外成骨细胞的分化和功能。在骨祖细胞中下调Drg2也会抑制Rac1激活。通过抑制Rac1活性可恢复下调Drg2所调控的破骨细胞和成骨细胞的分化。Drg2基因敲除小鼠由于破骨细胞数量显著减少而骨量增加，而成骨细胞数量未受到明显影响。此外，下调Drg2在体内可强烈抑制RANKL诱导的骨质流失。总之，Drg2通过Rac1激活调节破骨细胞和成骨细胞的分化及功能，从而有助于骨稳态。特别是，Drg2对破骨细胞的作用强大到足以在体内调节骨量；因此，Drg2在与骨质流失相关疾病中作为治疗靶点具有巨大潜力。
