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Osteoclasts (OC), the bone-resorbing cells, differentiate from macrophages under the influence of macrophage colony-stimulating factor (M-CSF) and receptor-activator of NF-<jats:italic>\u03ba<\/jats:italic>B ligand (RANKL). We found that M-CSF induced ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) auto-ADP-ribosylation in macrophages, a modification that marked ARTD1 for cleavage, and subsequently, for degradation upon RANKL exposure. We established that ARTD1 proteolysis was NLRP3 inflammasome-dependent, and occurred via the proteasome pathway. Since ARTD1 is cleaved at aspartate<jats:sup>214<\/jats:sup>, we studied the impact of ARTD1 rendered uncleavable by D214N substitution (ARTD1<jats:sup>D214N<\/jats:sup>) on skeletal homeostasis. ARTD1<jats:sup>D214N<\/jats:sup>, unlike wild-type ARTD1, was resistant to cleavage and degradation during osteoclastogenesis. As a result, ARTD1<jats:sup>D214N<\/jats:sup> altered histone modification and promoted the abundance of the repressors of osteoclastogenesis by interfering with the expression of B lymphocyte-induced maturation protein 1 (Blimp1), the master regulator of anti-osteoclastogenic transcription factors. Importantly, ARTD1<jats:sup>D214N<\/jats:sup>-expressing mice exhibited higher bone mass compared with controls, owing to decreased osteoclastogenesis while bone formation was unaffected. Thus, unless it is degraded, ARTD1 represses OC development through transcriptional regulation.<\/jats:p>","DOI":"10.1038\/cddis.2016.58","type":"journal-article","created":{"date-parts":[[2016,3,24]],"date-time":"2016-03-24T13:55:10Z","timestamp":1458827710000},"page":"e2153-e2153","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Poly-ADP-ribosylation-mediated degradation of ARTD1 by the NLRP3 inflammasome is a prerequisite for osteoclast maturation"],"prefix":"10.1038","volume":"7","author":[{"given":"C","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Alippe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S L","family":"Bonar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Civitelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Abu-Amer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M O","family":"Hottiger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Mbalaviele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,3,24]]},"reference":[{"key":"BFcddis201658_CR1","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev.pathmechdis.3.121806.151431","volume":"3","author":"DV Novack","year":"2008","unstructured":"Novack DV, Teitelbaum SL . 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