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

Exp Cell Res. 2020 Nov 1;396(1):112265. doi: 10.1016/j.yexcr.2020.112265. Epub 2020 Sep 6.

Abstract

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.

Keywords: Genetic animal models; Osteoclasts; PAK1; Rho GTPases; Trio.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Resorption / genetics*
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Cell Differentiation / drug effects
  • Female
  • Femur / cytology
  • Femur / drug effects
  • Femur / metabolism*
  • Gene Expression Regulation
  • 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 / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics*
  • RANK Ligand / pharmacology
  • Signal Transduction
  • cdc42 GTP-Binding Protein / genetics*
  • cdc42 GTP-Binding Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • rac1 GTP-Binding Protein / genetics*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Cdc42 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Neuropeptides
  • Phosphoproteins
  • RANK Ligand
  • Rac1 protein, mouse
  • Tnfsf11 protein, mouse
  • Trio protein, mouse
  • Macrophage Colony-Stimulating Factor
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein