Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma  

作　　者：Fengjuan Jiang Hui Liu Fengping Peng Zhaoyun Liu Kai Ding Jia Song Lijuan Li Jin Chen Qing Shao Siyang Yan Kim De Veirman Karin Vanderkerken Rong Fu 

机构地区：[1]Department of Hematology,Tianjin Medical University General Hospital,Tianjin 300052,China [2]Department of Hematology and Immunology-Myeloma Center Brussels,Vrije Universiteit Brussel,Brussels 1090,Belgium

出　　处：《Cancer Biology & Medicine》2021年第3期721-733,共13页癌症生物学与医学（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81770110,81900131,and 82000219);the Anticancer Major Special Project of Tianjin(Grant No.12ZCDZSY18000);the Tianjin Municipal Natural Science Foundation(Grant Nos.18JCYBJC27200 and 18JCQNJC80400);the Tianjin Education Commission Research Project(Grant Nos.2018KJ043 and 2018KJ045);the Tianjin Health and Family Planning Commission(Grant No.15KG150);the Youth Incubation Fund of Tianjin Medical University General Hospital(Grant No.ZYYFY2019020);the Tianjin Science and Technology Planning Project(Grant No.20YFZCSY00060)。

摘　　要：Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease.However,the mechanism of C3 a/C4 a in osteoclasts MM patients remains unclear.Methods:The formation and function of osteoclasts were analyzed after adding C3 a/C4 a in vitro.RNA-seq analysis was used to screen the potential pathways affecting osteoclasts,and the results were verified by Western blot,q RT-PCR,and pathway inhibitors.Results:The osteoclast area per view induced by 1μg/m L(mean±SD:50.828±12.984%)and 10μg/m L(53.663±12.685%)of C3 a was significantly increased compared to the control group(0μg/m L)(34.635±8.916%)(P<0.001 and P<0.001,respectively).The relative m RNA expressions of genes,OSCAR/TRAP/RANKL/cathepsin K,induced by 1μg/m L(median:5.041,3.726,1.638,and 4.752,respectively)and 10μg/m L(median:5.140,3.702,2.250,and 5.172,respectively)of C3 a was significantly increased compared to the control group(median:3.137,2.004,0.573,and 2.257,respectively)(1μg/m L P=0.001,P=0.003,P<0.001,and P=0.008,respectively;10μg/m L:P<0.001,P=0.019,P<0.001,and P=0.002,respectively).The absorption areas of the osteoclast resorption pits per view induced by 1μg/m L(mean±SD:51.464±11.983%)and 10μg/m L(50.219±12.067%)of C3 a was also significantly increased(33.845±8.331%)(P<0.001 and P<0.001,respectively)compared to the control.There was no difference between the C4 a and control groups.RNA-seq analysis showed that C3 a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase(PI3 K)signaling pathway.The relative expressions of PIK3 CA/phosphoinositide dependent kinase-1(PDK1)/serum and glucocorticoid inducible protein kinases(SGK3)genes and PI3 K/PDK1/p-SGK3 protein in the C3 a group were significantly higher than in the control group.The activation role of C3 a in osteoclasts of MM patients was reduced by the SGK inhibitor(EMD638683).Conclusions:C3 a

关 键 词：Multiple myeloma complement C3a OSTEOCLASTS PI3K/PDK1/SGK3 pathways SGK inhibitor 

分 类 号：R733.3[医药卫生—肿瘤]