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

Gu, Jiawen; Yang, Zhiwen; Yuan, Lichan; Guo, Shuyu; Wang, Dan; Zhao, Na; Li, Meng; Liu, Haojie; Chen, Wenjing; Ma, Junqing

doi:10.1016/j.yexcr.2020.112265

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…Trio has been shown to play important roles in cell migration, particularly during neuronal development, osteoclast differentiation, and endothelial growth. [60][61][62] Fgd1 acts in Cdc42-dependent cargo assembly at the Golgi, 63,64 and mutations in Fgd1 lead to X-linked faciogenital dysplasia. 65 The potential roles for these GEFs in ADA constitute novel functions for these proteins.…”

Section: Discussionmentioning

confidence: 99%

Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria

et al. 2022

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“…Rho GTPases play a key role in the formation of the sealing zone of osteoclasts and bone resorption 40 . Additionally, RhoA controls the rearrangement of podosomes, Rac1 promotes osteoclast production, and Cdc42 induces the survival of osteoclasts 41 . In this study, we found that 10 nM Cd induced the premature maturity of osteoclasts and promoted the formation of sealing zones; micromolar Cd inhibited the formation of osteoclasts, as well as the fusion of precursor cells.…”

Section: Discussionmentioning

confidence: 51%

Effect of cadmium on Rho GTPases signal transduction during osteoclast differentiation

Zhang

Liu

et al. 2022

Environmental Toxicology

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Osteoclasts are the key target cells for cadmium (Cd)-induced bone metabolism diseases, while Rho GTPases play an important role in osteoclast differentiation and bone resorption. To identify new therapeutic targets of Cd-induced bone diseases; we evaluated signal transduction through Rho GTPases during osteoclast differentiation under the influence of Cd. In osteoclastic precursor cells, 10 nM Cd induced pseudopodia stretching, promoted cell migration, upregulated the levels of Cdc42, and RhoQ mRNAs and downstream Rho-associated coiled-coil kinase 1 (ROCK1) and ROCK2 proteins, and downregulated the actin-related protein 2/3 (ARP2/3) levels.Cd at 2 and 5 μM shortened the pseudopodia, inhibited cell migration, and decreased ROCK1, ROCK2, and ARP2/3 protein levels; Cd at 5 μM also reduced the mRNA expression levels of Rac1, Rac2, and RhoU mRNAs and decreased the level of phosphorylated (p)-cofilin. In osteoclasts, 10 nM Cd induced the formation of sealing zones, slightly upregulated Cdc42 mRNA levels and ROCK2 and ARP2/3 protein levels and significantly reduced p-cofilin levels. Cd at 2 μM and 5 μM Cd blocked the fusion of precursor cells; and 5 μM Cd downregulated the expression levels of RhoB, Rac1, Rac3, and RhoU mRNAs, and ROCK1, p-cofilin and ARP2/3 protein levels, significantly. In vivo, Cd (at 5 or 25 mg/L) increased the levels of key proteins RhoA, Rac1/2/3, Cdc42, and RhoU and their mRNAs in bone marrow cells. In summary, the results suggested that Cd affected the differentiation process of osteoclast and altered the expression of several Rho GTPases, which might be crucial targets of Cd during the differentiation of osteoclasts.

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“…Osteoclasts were reduced in Rac1-deficient mice, which increased bone mass (Wang et al 2008 ). In addition, the mice which was conditionally ablated Trio (Rac1 and Cdc42 exchange factor Triple functional domain) in monocytes, showed increased bone mass due to impaired bone resorption caused by osteoclasts (Gu et al 2020 ). Additionally, we demonstrated in this work that mice with RhoA deletion in the osteoclast precursors and early stage of osteoclast development had a high bone mass phenotype, increased BV/TV and Tb.No, and reduced Tb.Sp, compared to wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

RhoA promotes osteoclastogenesis and regulates bone remodeling through mTOR-NFATc1 signaling

Wang

Zhang

et al. 2023

Mol Med

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Background The cytoskeletal architecture of osteoclasts (OCs) and bone resorption activity must be appropriately controlled for proper bone remodeling, which is associated with osteoporosis. The RhoA protein of GTPase plays a regulatory role in cytoskeletal components and contributes to osteoclast adhesion, podosome positioning, and differentiation. Although osteoclast investigations have traditionally been performed by in vitro analysis, however, the results have been inconsistent, and the significance of RhoA in bone physiology and pathology is still unknown. Methods We generated RhoA knockout mice by specifically deleting RhoA in the osteoclast lineage to understand more about RhoA’s involvement in bone remodeling. The function of RhoA in osteoclast differentiation and bone resorption and the mechanisms were assessed using bone marrow macrophages (BMMs) in vitro. The ovariectomized (OVX) mouse model was adopted to examine the pathological effect of RhoA in bone loss. Results Conditional deletion of RhoA in the osteoclast lineage causes a severe osteopetrosis phenotype, which is attributable to a bone resorption suppression. Further mechanistic studies suggest that RhoA deficiency suppresses Akt-mTOR-NFATc1 signaling during osteoclast differentiation. Additionally, RhoA activation is consistently related to the significant enhancement the osteoclast activity, which culminates in the development of an osteoporotic bone phenotype. Furthermore, in mice, the absence of RhoA in osteoclast precursors prevented occurring OVX-induced bone loss. Conclusion RhoA promoted osteoclast development via the Akt-mTOR-NFATc1 signaling pathway, resulting a osteoporosis phenotype, and that manipulating RhoA activity might be a therapeutic strategy for osteoporotic bone loss.

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

Cited by 7 publications

References 35 publications

Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria

Parallel kinase pathways stimulate actin polymerization at depolarized mitochondria

Effect of cadmium on Rho GTPases signal transduction during osteoclast differentiation

RhoA promotes osteoclastogenesis and regulates bone remodeling through mTOR-NFATc1 signaling

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