title: The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway.
abstract: Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Xulong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Shentao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Rheumatology & Immunology, Clinical Immunology Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing 100044, PR China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China. Electronic address: huihui_yuan@163.com.
authors.forename: Huihui
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China. Electronic address: zhao-wenming@163.com.
authors.forename: Wenming
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008811:Mice, Inbred DBA; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D018709:Statistics, Nonparametric
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D000072317:Polychlorinated Dibenzodioxins; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D000469:Alkaline Phosphatase
keywords: Aryl hydrocarbon receptor (Ahr); Differentiation; ERK signaling pathway; Osteoblasts; Proliferation; Rheumatoid arthritis (RA)