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

Abstract

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.

Phillygenin prevents osteoclast differentiation and bone loss by targeting RhoA

“…Conditional knockout of RhoA in osteoclast lineage mice was found to cause a severe osteopetrosis phenotype, likely due to the inhibition of osteoclast formation (Wang et al, 2023). In our study, we revealed Myosins, motor proteins, play a crucial role in the formation and rearrangement of F-actin rings.…”

“…By contrast, other studies have shown that RhoA promoted osteoclastogenesis. Conditional knockout of RhoA in osteoclast lineage mice was found to cause a severe osteopetrosis phenotype, likely due to the inhibition of osteoclast formation (Wang et al, 2023). In our study, we revealed that both RhoA inhibitor C3 and siRNA‐mediated knockdown of RhoA in mBMMs decreased the mRNA expression of NFATc1 and reduced OC formation (Figure 6d–i).…”

“…The function in osteoclasts has been studied using both in vitro and in vivo experiments. However, the obtained results are in conflict (Kim et al, 2021;Mizoguchi et al, 2013;Nakano et al, 2019;Park et al, 2018;Wang et al, 2023;Wu et al, 2017). Several experiments indicated that decreasing RhoA activity can enhance the signaling related to osteoclastogenesis (Mizoguchi et al, 2013;Wu et al, 2017).…”

“…Several experiments indicated that decreasing RhoA activity can enhance the signaling related to osteoclastogenesis (Mizoguchi et al, 2013; Wu et al, 2017). Conversely, a study found that the lack of RhoA blocked formation and activity of osteoclast in vivo (Wang et al, 2023). Thus, it was also important to reveal the role of RhoA in osteoclast and whether targeting RhoA could be an option for osteoporosis and other diseases related to bone resorption.…”

TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling

“…In mature osteoclasts MERTK signaling inhibited osteoclast podosome ring formation. Other authors showed that RHOA enhances osteoclastogenesis via mTOR-Nfatc1 and conditional knockout of RHOA resulted in increased bone mass 42,43 . In contrast, another study showed that activation of RHOA led to podosome belt dissolution and microtubule deacetylation thereby inhibiting osteoclast maturation 38 .…”