Nrf2 is a novel regulator of bone acquisition

• Published in: Bone (New York, N.Y.) Vol. 63; pp. 36 - 46
• Main Authors: Park, Cheol Kyu, Lee, Youngkyun, Kim, Kyun Ha, Lee, Zang Hee, Joo, Myungsoo, Kim, Hong-Hee
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2014; Elsevier
• Subjects: Animals; Biological and medical sciences; Chromatin Immunoprecipitation; Fundamental and applied biological sciences. Psychology; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; NFATc1; Nrf2; OPG; Orthopedics; Osteoblast; Osteoblasts - cytology; Osteoblasts - metabolism; Osteoclast; Osteogenesis - genetics; Osteogenesis - physiology; Osteoprotegerin - metabolism; Protein Binding; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Osteoblast; NF-κB; Osteoclast; NFATc1; Nrf2; OPG; Morphology; Transcription factor NFκB; Bone
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2014.01.025

Abstract Nuclear factor E2 p45-related factor 2 (Nrf2) is a transcription factor involved in the expression of cytoprotective genes induced by external stresses. We investigated the role of Nrf2 in osteoclast and osteoblast differentiation. Nrf2 knockdown or deletion increased osteoclastic differentiation from bone marrow-derived macrophages (BMMs) through the upregulation of NF-κB, c-Fos, and NFATc1 transcription factors. Nrf2 also inhibited osteoblast differentiation and mineralization via suppression of key regulatory proteins, such as Runx2, osteocalcin, and osterix. Micro-computed tomography and histomorphometric analyses showed an increase in bone mass of Nrf2 knockout compared to that of wild type mice. In addition, the mineral apposition rate and the number of osteoblasts in bone were higher in Nrf2 knockout mice. However, bone resorption parameters, namely DPD and CTX levels, were not affected by Nrf2 deletion. In a coculture condition where calvarial osteoblasts and BMMs from wild type and Nrf2 knockout mice were grown, deletion of Nrf2 in osteoblasts markedly reduced osteoclast formation. This effect was due to an increase in OPG expression in Nrf2 knockout osteoblasts. Taken as a whole, these results indicate that Nrf2 is intrinsically inhibitory to both osteoblast and osteoclast differentiation but its effect on osteoblasts is dominant to its effect on osteoclasts in vivo.