<br>VSIG4 通过增强 Nrf2 依赖性抗氧化反应来抑制 RANKL 诱导的破骨细胞生成，对抗活性氧的产生,International Journal of Biological Macromolecules

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VSIG4 通过增强 Nrf2 依赖性抗氧化反应来抑制 RANKL 诱导的破骨细胞生成，对抗活性氧的产生
International Journal of Biological Macromolecules ( IF 7.7 ) Pub Date : 2024-01-11 , DOI: 10.1016/j.ijbiomac.2024.129357
Jiansen Miao ₁ , Yiting Tu ₁ , Junchen Jiang ₂ , Rufeng Ren ₂ , Qihang Wu ₁ , Haibo Liang ₁ , Tengjie Wang ₁ , Binghao Lin ₁ , Jingtao Wu ₁ , Youjin Pan ₃ , Xiangyang Wang ₁ , Haiming Jin ₁

Affiliation

骨质疏松症是一种普遍存在的系统性骨骼疾病，尤其影响绝经后妇女，主要是由于破骨细胞的过度产生和激活所致。然而，目前临床上使用的抗骨质疏松药物可能会产生一定的副作用。因此，有必要进一步揭示调节破骨细胞分化的潜在机制并确定骨质疏松症治疗的新靶点。这项研究揭示了 VSIG 家族成员中 VSIG4 表达下降最显着。 VSIG4过表达显着抑制RANKL诱导的破骨细胞生成和骨吸收功能。从机制上讲，蛋白质印迹和免疫荧光测定结果均表明 VSIG4 过表达减弱了破骨细胞标记基因的表达，并抑制了 MAPK 和 NF-κB 信号通路的激活。此外，VSIG4过表达可以抑制活性氧（ROS）的产生，并通过与Keap1相互作用刺激Nrf2及其下游抗氧化酶的表达。值得注意的是，一种有效的 Nrf2 抑制剂 ML385 可以逆转 VSIG4 对破骨细胞分化的抑制作用。与这些发现一致，VSIG4 过表达也减轻了 OVX 诱导的骨质流失，并减弱了体内破骨细胞的活化。总之，我们的结果表明 VSIG4 有希望成为解决绝经后骨质疏松症的新靶点。这是通过增强 Nrf2 依赖性抗氧化反应来抑制破骨细胞的形成来实现的。

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VSIG4 inhibits RANKL-induced osteoclastogenesis by enhancing Nrf2-dependent antioxidant response against reactive oxygen species production

Osteoporosis is a prevalent systemic skeletal disorder, particularly affecting postmenopausal women, primarily due to excessive production and activation of osteoclasts. However, the current anti-osteoporotic drugs utilized in clinical practice may lead to certain side effects. Therefore, it is necessary to further unravel the potential mechanisms regulating the osteoclast differentiation and to identify novel targets for osteoporosis treatment. This study revealed the most significant decline in VSIG4 expression among the VSIG family members. VSIG4 overexpression significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanistically, both western blot and immunofluorescence assay results demonstrated that VSIG4 overexpression attenuated the expression of osteoclast marker genes and dampened the activation of MAPK and NF-κB signaling pathways. Furthermore, VSIG4 overexpression could inhibit the generation of reactive oxygen species (ROS) and stimulate the expression of Nrf2 along with its downstream antioxidant enzymes via interaction with Keap1. Notably, a potent Nrf2 inhibitor, ML385, could reverse the inhibitory effect of VSIG4 on osteoclast differentiation. In line with these findings, VSIG4 overexpression also mitigated bone loss induced by OVX and attenuated the activation of osteoclasts in vivo. In conclusion, our results suggest that VSIG4 holds promise as a novel target for addressing postmenopausal osteoporosis. This is achieved by suppressing osteoclast formation via enhancing Nrf2-dependent antioxidant response against reactive oxygen species production.

更新日期：2024-01-11

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