Nrf2 deficiency aggravates the increase in osteoclastogenesis and bone loss induced by inorganic arsenic
| Autor: | Jingbo Pi, Lu Li, Yuanyuan Xu, Jingkun Jia, Masayuki Yamamoto, Tingfeng Li, Yongxin Sun, Yongyong Hou, Jingqi Fu, Huihui Wang, Yang Yang, Zhixuan Hong, Zhiyuan Liu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
inorganic chemicals
0301 basic medicine medicine.medical_specialty Arsenites NF-E2-Related Factor 2 p38 mitogen-activated protein kinases Osteoporosis Osteoclasts chemistry.chemical_element Toxicology medicine.disease_cause environment and public health Bone resorption Mice 03 medical and health sciences 0302 clinical medicine Osteogenesis Osteoclast Internal medicine medicine Animals Femur Arsenic Mice Knockout Pharmacology integumentary system Chemistry Activator (genetics) respiratory system medicine.disease Sodium Compounds Mice Inbred C57BL Oxidative Stress RAW 264.7 Cells 030104 developmental biology medicine.anatomical_structure Endocrinology 030220 oncology & carcinogenesis Phosphorylation Female Bone Remodeling Oxidative stress Signal Transduction |
| Zdroj: | Toxicology and Applied Pharmacology. 367:62-70 |
| ISSN: | 0041-008X |
| Popis: | Arsenic exposure increases the risk of various bone disorders. For instance, chronic exposure to low level arsenic can cause bone resorption by promoting osteoclast differentiation. Osteoclast precursor cells produce hydrogen peroxide after low level arsenic exposure and then undergo differentiation, producing cells which break down bone matrix. Nuclear factor E2-related factor 2 (Nrf2) regulates receptor activator of nuclear factor-κB dependent osteoclastogenesis by modulating intracellular reactive oxygen species (ROS) signaling via expression of cytoprotective enzymes. Here we tested the hypothesis that loss of Nrf2 will increase arsenic-induced bone loss. We treated 40 week-old Nrf2+/+ and Nrf2−/− mice with 5 ppm arsenic in the drinking water, which produces a blood arsenic level similar to humans living in areas where arsenic exposure is endemic. After 4 months, Micro-CT and dual-energy x-ray analysis revealed a drastic overall decrease in the bone volume with arsenic treatment in mice lacking Nrf2. Deficiency of Nrf2 in RAW 264.7 cells or bone marrow-derived macrophages (BMMs) promoted arsenic-induced osteoclast differentiation. Lack of Nrf2 increases arsenic-induced ROS levels and phosphorylation of p38. N-Acetyl-cysteine and SB203580 pretreatment essentially abolished arsenic-induced phosphorylation of p38 and reversed arsenic-induced increased osteoclast differentiation in Nrf2 deficiency. Taken together, our data suggest that loss of Nrf2 causes increased oxidative stress and enhanced susceptibility to arsenic-induced bone loss. |
| Databáze: | OpenAIRE |
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