NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion.

Peter Sang Uk Park,Kyung-Hyun Park-Min,Haemin Kim,Se Hwan Mun,Steven L Zeng,Seyeon Bae

doi:10.3390/cells9092133

Peter Sang Uk Park, Kyung-Hyun Park-Min + Show 4 more

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https://doi.org/10.3390/cells9092133

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Journal: Cells	Publication Date: Sep 21, 2020
Citations: 12	License type: CC BY 4.0

Affiliation: Hospital for Special Surgery, Cornell University

Abstract

Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion.

Highlights

In prevalent bone diseases such as rheumatoid arthritis and osteoporosis, overly-activated osteoclasts are the primary culprits of excessive bone loss and erosion [1,2]
As an effort to further uncover the mechanisms behind osteoclastogenesis that could be therapeutically targeted, we recently revealed the critical role of MYC in osteoclast formation and metabolic reprogramming in osteoclasts [16,17]
We demonstrate that nuclear factor erythroid 2-related factor 2 (NRF2) acts as a novel upstream regulator of MYC by controlling the activation of extracellular signal-regulated protein kinase (ERK) and p38 during RANKL-induced osteoclastogenesis

Summary

Introduction

In prevalent bone diseases such as rheumatoid arthritis and osteoporosis, overly-activated osteoclasts are the primary culprits of excessive bone loss and erosion [1,2]. Osteoclasts are multinucleated, bone-resorbing cells differentiated from myeloid lineage precursor cells with the stimulus from macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) [3,4,5,6,7] Upon binding to their receptors, M-CSF and RANKL induce mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated protein kinase (ERK) and p38 to activate pathways in the proliferation and differentiation of osteoclast precursor cells [8]. Downstream of these pathways lies the master transcriptional factor nuclear factor of activated T cells (NFATc1), which promotes the transcription of essential genes for osteoclast function in bone resorption and polarization [9,10].

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