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The osteoclast is the only cell in the body capable of resorbing and degrading the mineralized bone matrix. Osteoclast formation from monocytic precursors is governed by the actions of two key cytokines macrophage\u2010colony\u2010stimulating factor and receptor activator of nuclear factor\u2010\u03baB ligand (RANKL). Binding of RANKL binding to receptor RANK initiates a series of downstream signaling responses leading to monocytic cell differentiation and fusion, and subsequent mature osteoclast bone resorption and survival. The phosphoinositide\u20103\u2010kinase (PI3K)\u2010protein kinase B (Akt) signaling cascade is one such pathway activated in response to RANKL. The 3\u2010phosphoinositide\u2010dependent protein kinase 1 (PDK1), is considered the master upstream lipid kinase of the PI3K\u2010Akt cascade. PDK1 functions to phosphorylate and partially activate Akt, triggering the activation of downstream effectors. However, the role of PDK1 in osteoclasts has yet to be clearly defined. In this study, we specifically deleted the <jats:italic>PDK1<\/jats:italic> gene in osteoclasts using the cathepsin\u2010K promoter driven <jats:italic>Cre\u2010LoxP<\/jats:italic> system. We found that the specific genetic ablation of PDK1 in osteoclasts leads to an osteoclast\u2010poor osteopetrotic phenotype in mice. In vitro cellular assays further confirmed the impairment of osteoclast formation in response to RANKL by <jats:italic>PDK1<\/jats:italic>\u2010deficient bone marrow macrophage (BMM) precursor cells. <jats:italic>PDK1<\/jats:italic>\u2010deficient BMMs exhibited reduced ability to reorganize actin cytoskeleton to form a podosomal actin belt as a result of diminished capacity to fuse into giant multinucleated osteoclasts. Notably, biochemical analyses showed that <jats:italic>PDK1<\/jats:italic> deficiency attenuated the phosphorylation of Akt and downstream effector GSK3\u03b2, and reduced induction of NFATc1. GSK3\u03b2 is a reported negative regulator of NFATc1. GSK3\u03b2 activity is inhibited by Akt\u2010dependent phosphorylation. Thus, our data provide clear genetic and mechanistic insights into the important role for PDK1 in osteoclasts.<\/jats:p>","DOI":"10.1002\/jcb.29677","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T12:48:25Z","timestamp":1581511705000},"page":"4542-4557","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["PDK1 is important lipid kinase for RANKL\u2010induced osteoclast formation and function via the regulation of the Akt\u2010GSK3\u03b2\u2010NFATc1 signaling cascade"],"prefix":"10.1002","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0417-4916","authenticated-orcid":false,"given":"Dongliang","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Spine Osteopathia, The First Affiliated Hospital of Guangxi Medical University Guangxi Medical University Nanning Guangxi 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University  Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaofeng","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Public Hygiene of Guangxi Medical University  Guangxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaohui","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Spine Osteopathia, The First Affiliated Hospital of Guangxi Medical University Guangxi Medical University Nanning Guangxi China"},{"name":"Research Centre for Regenerative Medicine and Guangxi Key Laboratory of Regenerative Medicine Guangxi Medical University Nanning Guangxi 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