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In vitro assays identified two RANK intracellular motifs that bind TRAFs: PVQEET560\u2013565 (Motif 2) and PVQEQG604\u2013609 (Motif 3), which potently mediate osteoclast formation in vitro. To validate the in vitro findings, we have generated knock-in (KI) mice harboring inactivating mutations in RANK Motifs 2 and 3. Homozygous KI (RANKKI\/KI) mice are born at the predicted Mendelian frequency and normal in tooth eruption. However, RANKKI\/KI mice exhibit significantly more trabecular bone mass than age- and sex-matched heterozygous KI (RANK+\/KI) and wild-type (RANK+\/+) counterparts. Bone marrow macrophages (BMMs) from RANKKI\/KI mice do not form osteoclasts when they are stimulated with macrophage colony-stimulating factor (M-CSF) and RANKL in vitro. RANKL is able to activate the NF-\u03baB, ERK, p38, and JNK pathways in RANKKI\/KI BMMs, but it cannot stimulate c-Fos or NFATc1 in the RANKKI\/KI cells. Previously, we showed that RANK signaling plays an important role in Porphyromonas gingivalis (Pg)-mediated osteoclast formation by committing BMMs into the osteoclast lineage. Here, we show that RANKL-primed RANKKI\/KI BMMs are unable to differentiate into osteoclasts in response to Pg stimulation, indicating that the two RANK motifs are required for Pg-induced osteoclastogenesis. Mechanistically, RANK Motifs 2 and 3 facilitate Pg-induced osteoclastogenesis by stimulating c-Fos and NFATc1 expression during the RANKL pretreatment phase as well as rendering c-Fos and NFATc1 genes responsive to subsequent Pg stimulation. Cell-penetrating peptides (CPPs) conjugated with RANK segments containing Motif 2 or 3 block RANKL- and Pg-mediated osteoclastogenesis. The CPP conjugates abrogate RANKL-stimulated c-Fos and NFATc1 expression but do not affect RANKL-induced activation of NF-\u03baB, ERK, p38, JNK, or Akt signaling pathway. Taken together, our current findings demonstrate that RANK Motifs 2 and 3 play pivotal roles in osteoclast formation in vivo and mediate Pg-induced osteoclastogenesis in vitro.<\/jats:p>","DOI":"10.1002\/jbmr.3810","type":"journal-article","created":{"date-parts":[[2019,6,7]],"date-time":"2019-06-07T14:42:14Z","timestamp":1559918534000},"page":"1938-1951","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Specific RANK Cytoplasmic Motifs Drive Osteoclastogenesis"],"prefix":"10.1093","volume":"34","author":[{"given":"Yuyu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham Birmingham AL USA"},{"name":"State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University Chengdu People's Republic of 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Alabama at Birmingham Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry School of Dentistry, University of Alabama at Birmingham Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-479X","authenticated-orcid":false,"given":"Xu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham Birmingham AL 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