title: TRP14 inhibits osteoclast differentiation via its catalytic activity.
abstract: We previously reported the inhibitory role of thioredoxin-related protein of 14 kDa (TRP14), a novel disulfide reductase, in nuclear factor-κB (NF-κB) activation, but its biological function has remained to be explored. Here, we evaluated the role of TRP14 in the differentiation and function of osteoclasts (OCs), for which NF-κB and cellular redox regulation have been known to be crucial, using RAW 264.7 macrophage cells expressing wild-type TRP14 or a catalytically inactive mutant, as well as its small interfering RNA. TRP14 depletion enhanced OC differentiation, actin ring formation, and bone resorption, as well as the accumulation of reactive oxygen species (ROS). TRP14 depletion promoted the activation of NF-κB, c-Jun NH2-terminal kinase, and p38, the expression of c-Fos, and the consequent induction of nuclear factor of activated T cell, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. However, pretreatment with N-acetylcysteine or diphenylene iodonium significantly reduced the OC differentiation, as well as the ROS accumulation and NF-κB activation, that were enhanced by TRP14 depletion. Furthermore, receptor activator of NF-κB ligand (RANKL)-induced ROS accumulation, NF-κB activation, and OC differentiation were inhibited by the ectopic expression of wild-type TRP14 but not by its catalytically inactive mutant. These results suggest that TRP14 regulates OC differentiation and bone resorption through its catalytic activity and that enhancing TRP14 may present a new strategy for preventing bone resorption diseases.
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Sohyun
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Huh
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, College of Natural Science, Sejong University, Seoul, Republic of Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Shim
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Republic of Korea jeongw@ewha.ac.kr.
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009861:Onium Compounds / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D016328:NF-kappa B; D009861:Onium Compounds; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D013879:Thioredoxins; C007517:diphenyleneiodonium; D000111:Acetylcysteine