Rho-GEF trio regulates osteoclast differentiation and function by Rac1/Cdc42

• Published in: Experimental cell research Vol. 396; no. 1; p. 112265
• Main Authors: Gu, Jiawen, Yang, Zhiwen, Yuan, Lichan, Guo, Shuyu, Wang, Dan, Zhao, Na, Meng, Li, Liu, Haojie, Chen, Wenjing, Ma, Junqing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2020
• Subjects: Animals; Bone Resorption - genetics; Bone Resorption - metabolism; Bone Resorption - pathology; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Differentiation - drug effects; Female; Femur - cytology; Femur - drug effects; Femur - metabolism; Gene Expression Regulation; Genetic animal models; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Macrophage Colony-Stimulating Factor - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Neuropeptides - genetics; Neuropeptides - metabolism; Osteoclasts; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteogenesis - genetics; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; PAK1; Phosphoproteins - deficiency; Phosphoproteins - genetics; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; RANK Ligand - pharmacology; Rho GTPases; Signal Transduction; Trio; M-CSF; JNK; Itgβ3; P1NP; c-Fos; Ctsk; RANK; TRAP; Mitf; BMMs; Pu.1; Genetic animal models; PAK1; Rac1; Nfatc1; OCs; Cdc42; Car2; Trio; MAPK; Mmp9; Rho GTPases; Osteoclasts; CTX-1; ERK
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2020.112265

Many bone diseases result from abnormal bone resorption by osteoclasts (OCs). Studying OC related regulatory genes is necessary for the development of new therapeutic strategies. Rho GTPases have been proven to regulate OC differentiation and function and only mature OCs can carry out bone resorption. Here we demonstrate that Rac1 and Cdc42 exchange factor Triple functional domain (Trio) is critical for bone resorption caused by OCs. In this study, we created LysM-Cre;Triofl/fl conditional knockout mice in which Trio was conditionally ablated in monocytes. LysM-Cre;Triofl/fl mice showed increased bone mass due to impaired bone resorption caused by OCs. Furthermore, our in vitro analysis indicated that Trio conditional deficiency significantly suppressed OC differentiation and function. At the molecular level, Trio deficiency significantly inhibited the expression of genes critical for osteoclastogenesis and OC function. Mechanistically, our researches suggested that perturbed Rac1/Cdc42-PAK1-ERK/p38 signaling could be used to explain the lower ability of bone resorption in CKO mice. Taken together, this study indicates that Trio is a regulator of OCs. Studying the role of Trio in OCs provides a potential new insight for the treatment of OC related bone diseases. •This is the first study to report that Trio participates in regulating bone resorption.•The LysM-Cre;Triofl/fl mice were created for in vivo study.•Trio regulates the differentiation and function of OCs through Rac1/Cdc42-PAK1-ERK/p38 signaling.•Studying Trio in OCs can provide new ideas for the treatment of related bone diseases.