Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, 1229 Gudun Road, Hangzhou, 310030, China.
Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
Mol Med. 2023 Apr 5;29(1):49. doi: 10.1186/s10020-023-00638-1.
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.
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.
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.
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.
破骨细胞（OC）的细胞骨架结构和骨吸收活性必须得到适当的控制，以进行适当的骨重塑，这与骨质疏松症有关。GTP 酶的 RhoA 蛋白在细胞骨架成分中起调节作用，并有助于破骨细胞黏附、足突定位和分化。尽管破骨细胞的研究传统上是通过体外分析进行的，但是结果一直不一致，并且 RhoA 在骨生理学和病理学中的意义仍然未知。
我们通过特异性地在破骨细胞谱系中删除 RhoA 来生成 RhoA 敲除小鼠，以更深入地了解 RhoA 参与骨重塑的情况。使用体外的骨髓巨噬细胞（BMM）评估 RhoA 在破骨细胞分化和骨吸收中的功能及其机制。采用去卵巢（OVX）小鼠模型来研究 RhoA 在骨丢失中的病理作用。
破骨细胞谱系中 RhoA 的条件性缺失会导致严重的骨质增生表型，这归因于骨吸收的抑制。进一步的机制研究表明，RhoA 缺乏会抑制破骨细胞分化过程中的 Akt-mTOR-NFATc1 信号通路。此外，RhoA 的激活与破骨细胞活性的显著增强密切相关，最终导致骨质疏松性骨表型的发展。此外，在小鼠中，破骨细胞前体细胞中 RhoA 的缺失可防止 OVX 诱导的骨丢失的发生。
RhoA 通过 Akt-mTOR-NFATc1 信号通路促进破骨细胞的发育，导致骨质疏松表型，并且操纵 RhoA 活性可能是治疗骨质疏松性骨丢失的一种策略。
