title: NADPH oxidase gp91phoxcontributes to RANKL-induced osteoclast differentiation by upregulating NFATc1.
abstract: Bone-marrow derived monocyte-macrophages (BMMs) differentiate into osteoclasts by M-CSF along subsequent RANKL stimulation possibly in collaboration with many other unknown cytokines released by pre- or mature osteoblasts. The differentiation process requires receptor activator of nuclear factor kappa-B ligand (RANKL)/RANK signaling and reactive oxygen species (ROS) such as superoxide anion (O2•-). Gp91phox, a plasma membrane subunit of NADPH oxidase (Nox), is constitutively expressed in BMMs and plays a major role in superoxide anion production. In this study, we found that mice deficient in gp91phox(gp91phox-/-) showed defects in osteoclast differentiation. Femurs of these mice produced osteoclasts at about 70% of the levels seen in femurs from wild-type mice, and accordingly exhibited excessive bone density. This abnormal bone growth in the femurs of gp91phox-/-mice resulted from impaired osteoclast differentiation. In addition, gp91phox-/-mice were defective for RANKL-induced expression of nuclear factor of activated T cells c1 (NFATc1). However, H2O2treatment compensated for gp91phoxdeficiency in BMMs, almost completely rescuing osteoclast differentiation. Treating wild-type BMMs with antioxidants and superoxide inhibitors resulted in a differentiation defect resembling the phenotype of gp91phox-/-BMMs. Therefore, our results demonstrate that gp91phox-derived superoxide is important for promoting efficient osteoclast differentiation by inducing NFATc1 as a downstream signaling mediator of RANK.
authors.affiliation: Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea.
authors.forename: In Soon
authors.initials: IS
authors.lastname: Kang
authors.affiliation: Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea.|Convergent Research Center for Metabolism and Immunoregulation, Inha University, Incheon 22212, Korea.
authors.forename: Chaekyun
authors.initials: C
authors.lastname: Kim
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C105949:Pirb protein, mouse; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C505689:Tnfsf11 protein, mouse