The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

• Published in: Toxicology and applied pharmacology Vol. 280; no. 3; pp. 502 - 510
• Main Authors: Yu, Haitao, Du, Yuxuan, Zhang, Xulong, Sun, Ying, Li, Shentao, Dou, Yunpeng, Li, Zhanguo, Yuan, Huihui, Zhao, Wenming
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ALKALINE PHOSPHATASE; Alkaline Phosphatase - metabolism; Animals; Arthritis, Experimental - metabolism; Aryl hydrocarbon receptor (Ahr); Azo Compounds - pharmacology; Biological and medical sciences; Blotting, Western; Bone and Bones - cytology; Bone and Bones - metabolism; Bone Density - physiology; BONE MINERAL DENSITY; Cell Line; CELL PROLIFERATION; Cell Proliferation - physiology; CHEMILUMINESCENCE; COLLAGEN; CONNECTIVE TISSUE CELLS; Differentiation; Diseases of the osteoarticular system; EOSIN; ERK signaling pathway; HEAT-SHOCK PROTEINS; HYDROCARBONS; Immunohistochemistry; Inflammatory joint diseases; LUCIFERASE; Male; MAP Kinase Signaling System - physiology; Medical sciences; MESSENGER-RNA; MICE; Mice, Inbred DBA; Osteoblasts; Osteoblasts - cytology; Osteoblasts - metabolism; PHOSPHORYLATION; Polychlorinated Dibenzodioxins - pharmacology; Proliferation; Pyrazoles - pharmacology; RECEPTORS; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - metabolism; RHEUMATIC DISEASES; Rheumatoid arthritis (RA); Specific Pathogen-Free Organisms; Statistics, Nonparametric; Toxicology; C II; ALP; IFA; ERK signaling pathway; TCDD; Ahr; XRE; Osteoblasts; Aryl hydrocarbon receptor (Ahr); FBS; BMD; CIA; Rheumatoid arthritis (RA); IL; DAB; HSP; qRT-PCR; AIP; TBST; ARNT; DAPI; pNPP; Proliferation; EDTA; PVDF; ECL; RA; Differentiation; HE; CH-223191; CFA; ERK; Cell proliferation; Extracellular signal-regulated protein kinase; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Osteoarticular system; Signal transduction; Signaling pathway; Osteoblast; Immunopathology; Hydrocarbon; Enzyme; Transferases; Mitogen-activated protein kinase; Cell differentiation; Ah receptor; Aryl hydrocarbon receptor; Chronic; Rheumatoid arthritis; Bone
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.08.025

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. •The upregulation of Ahr was localized in osteoblasts of CIA mice.•The overexpression of Ahr suppressed osteoblast development.•The Ahr activated ERK signaling pathway to exacerbate bone erosion.