Dimethyl fumarate inhibits osteoclasts via attenuation of reactive oxygen species signalling by augmented antioxidation

Abstract

Bone destructive diseases are common worldwide and are caused by dysregulation of osteoclast formation and activation. During osteoclastogenesis, reactive oxygen species (ROS) play a role in the intracellular signalling triggered by receptor activator of nuclear factor-jB ligand (RANKL) stimulation. Previously, we demonstrated that induction of antioxidant enzymes by Nrf2 activation using Nrf2-gene transfer, an ETGEpeptide or polyphenols, successfully ameliorated RANKL-dependent osteoclastogenesis. Dimethyl fumarate (DMF) has been shown to activate Nrf2 signalling and has been lately used in clinical trials for neurodegenerative diseases. In this study, we hypothesized that Nrf2 activation by DMF would inhibit osteoclastogenesis and bone destruction via attenuation of intracellular ROS signalling through antioxidant mechanisms. RAW 264.7 cells were used as osteoclast progenitor cells. We found that DMF induced Nrf2 translocation to the nucleus, augmented Nrf2 promoter-luciferase reporter activity and increased antioxidant enzyme expression. Using flow cytometry, we found that DMF attenuated RANKL-mediated intracellular ROS generation, which resulted in the inhibition of RANKL-mediated osteoclastogenesis. Local DMF injection into the calvaria of male BALB/c mice resulted in attenuated bone destruction in lipopolysaccharide-treated mice. In conclusion, we demonstrated in a preclinical setting that DMF inhibited RANKL-mediated osteoclastogenesis and bone destruction via induction of Nrf2-mediated transcription of antioxidant genes and consequent decrease in intracellular ROS levels. Our results suggest that DMF may be a promising inhibitor of bone destruction in diseases like periodontitis, rheumatoid arthritis and osteoporosis.Keywords: osteoclast Nrf2 dimethyl fumarate receptor activator of nuclear factor-kB ligand oxidative stress reactive oxygen species antioxidant response HO-1

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

“…B ). Of note, we observed normalization of ROS production in Dpp3 KO OCPs also after treatment with dimethyl fumarate (DMF), which is a known agonist of the Nrf2 pathway; in parallel, no change in ROS levels was found in WT OCPs upon DMF treatment (Supporting Fig. 4a in File S1).…”

Metabolic Checkpoints in Rheumatoid Arthritis

“…With regard to fumarate, the methyl ester dimethyl fumarate (DMF) has been approved for the treatment of relapsing multiple sclerosis (MS) Gold et al, 2012). Interestingly DMF has been reported to reduce osteoclastogenesis and bone destruction via increasing the expression of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant genes and decreasing reactive oxygen species (ROS) levels (Yamaguchi et al, 2018). The role of itaconate in RA is still debated.…”

<p>Zn-Incorporated TiO2 Nanotube Surface Improves Osteogenesis Ability Through Influencing Immunomodulatory Function of Macrophages</p>

“…TGF-beta accelerates the formation of fibrous wraps and separates inflamed tissue from normal tissue, to reduce the formation of inflammatory granulation tissue, 70 while the increase of HO-1 can effectively inhibit the excessive action of osteoclasts. [71][72][73] Macrophages of the M1 and M2 phenotypes are indispensable in osteogenesis. Therefore, some scholars suggested that the key factor in determining macrophage-induced osteogenic or osteoclastic effects is the macrophage switch pattern rather than the specific macrophage phenotype.…”