Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Eiko SakaiTakayuki Tsukuba

Abstract

Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)-mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reducedin vivowithout severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclastsin vitroviaattenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression ofMafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negat...Continue Reading

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Citations

Mar 16, 2018·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Eiki YoshidaMasayuki Yamamoto
Dec 7, 2018·Frontiers in Genetics·Yaroslav R EfremovSergey S Bogachev
Feb 23, 2021·Cell Proliferation·Jiachao GuoJingfan Shao

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