title: Nrf2 is a novel regulator of bone acquisition.
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.
authors: Department of Cell and Developmental Biology, BK21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Cheol Kyu
authors: CK
authors: Park
authors: Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors: Youngkyun
authors: Y
authors: Lee
authors: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors: Kyun Ha
authors: KH
authors: Kim
authors: Department of Cell and Developmental Biology, BK21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Zang Hee
authors: ZH
authors: Lee
authors: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 626-870, Republic of Korea. Electronic address: mjoo@pusan.ac.kr.
authors: Myungsoo
authors: M
authors: Joo
authors: Department of Cell and Developmental Biology, BK21 Program, Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea. Electronic address: hhbkim@snu.ac.kr.
authors: Hong-Hee
authors: HH
authors: Kim
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics* / Q000502:physiology; D053244:Osteoprotegerin / Q000378:metabolism; D011485:Protein Binding
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053244:Osteoprotegerin
keywords: NF-κB; NFATc1; Nrf2; OPG; Osteoblast; Osteoclast