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Recently, the optineurin (OPTN) gene has been implicated in PDB, and global OPTN knockout mice (<jats:italic>Optn<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) were shown to exhibit increased formation of osteoclasts (osteoclastogenesis). Growing evidence, including our own, has demonstrated that intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can act as signaling molecules to promote osteoclastogenesis. Here, we report that OPTN interacts with nuclear factor erythroid-derived factor 2-related factor 2 (NRF2), the master regulator of the antioxidant response, defining a pathway through which RANKL-induced ROS could be regulated for osteoclastogenesis. In this study, monocytes from<jats:italic>Optn<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>and wild-type (<jats:italic>Optn<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>) mice were utilized to differentiate into osteoclasts, and both qRT-PCR and tartrate-resistant acid phosphatase (TRAP) staining showed that the<jats:italic>Optn<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>monocytes exhibited enhanced osteoclastogenesis compared to the<jats:italic>Optn<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>cells. CellROX<jats:sup>\u00ae<\/jats:sup>staining, qRT-PCR, and Western blotting indicated that OPTN deficiency reduced the basal expression of<jats:italic>Nrf2<\/jats:italic>, inhibited the expression of NRF2-responsive antioxidants, and increased basal and RANKL-induced intracellular ROS levels, leading to enhanced osteoclastogenesis. Coimmunoprecipitation (co-IP) showed direct interaction, and immunofluorescence staining showed perinuclear colocalization of the OPTN-NRF2 granular structures during differentiation. Finally, curcumin and the other NRF2 activators attenuated the hyperactive osteoclastogenesis induced by OPTN deficiency. Collectively, our findings reveal a novel OPTN-mediated mechanism for regulating the NRF2-mediated antioxidant response in osteoclasts and extend the therapeutic potential of OPTN in the aging process resulting from ROS-triggered oxidative stress, which is associated with PDB and many other degenerative diseases.<\/jats:p>","DOI":"10.1038\/s12276-021-00596-w","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T07:57:58Z","timestamp":1618559878000},"page":"667-680","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response"],"prefix":"10.1038","volume":"53","author":[{"given":"Peng","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangxiang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4691-2665","authenticated-orcid":false,"given":"Lufei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-7587","authenticated-orcid":false,"given":"Tai-Hsien","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Joon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry C.","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Chang","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"596_CR1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1615\/CritRevEukarGeneExpr.v19.i3.40","volume":"19","author":"E Seeman","year":"2009","unstructured":"Seeman, E. 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