Yuan X, Cao J, Liu T, Li Y-P, Scannapieco F, He X, Oursler M J, Zhang X, Vacher J, Li C, Olson D, Yang S
Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, NY 14214, USA.
USDA Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA.
Cell Death Differ. 2015 Dec;22(12):2046-57. doi: 10.1038/cdd.2015.45. Epub 2015 Apr 24.
Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca(2+) oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12(fl/fl) cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss.
G蛋白信号调节因子（Rgs）在控制各种细胞过程（如细胞分化）中起关键作用。Rgs蛋白如何调节破骨细胞（OC）分化、功能和骨稳态尚不清楚。先前的研究表明，Rgs家族中最大的蛋白Rgs12主要在破骨细胞中表达，并在体外调节破骨细胞分化。为了进一步了解Rgs12在体内破骨细胞分化和骨疾病中的作用及机制，我们通过使用诱导型Mx1-Cre和CD11b-Cre创建了破骨细胞靶向的Rgs12基因敲除小鼠。造血细胞或特异性破骨细胞前体中Rgs12的缺失导致骨量增加，破骨细胞数量减少。Rgs12的缺失损害了破骨细胞的分化和功能，导致钙离子振荡受损，活化T细胞核因子（NFAT）2表达降低。野生型成骨细胞的引入并不能挽救有缺陷的破骨细胞生成。NFAT2的异位表达挽救了CD11b;Rgs12(fl/fl)细胞中有缺陷的破骨细胞分化，并促进了正常破骨细胞分化。此外，Rgs12的缺失显著抑制了卵巢切除和脂多糖诱导的骨质流失的Rgs12缺陷小鼠的病理性破骨细胞生成和骨破坏。因此，我们的研究结果表明，Rgs12是破骨细胞分化和功能的重要调节因子，并确定Rgs12是骨质疏松症和炎症性骨质流失的潜在治疗靶点。
