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While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8\u2014and its paralog CDK19\u2014have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8\/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8\/19 inhibitor affects cancellous bone healing in rats. CDK8\/19 inhibitors did not alter the proliferation of neither mouse bone marrow\u2013derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor \u03ba\u0392 (NF\u2010\u03baB) ligand (RANKL)\u2010induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8\/19, concomitant with reduced tartrate\u2010resistant acid phosphatase (TRAP) activity and C\u2010terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF\u2010\u03baB, nuclear factor of activated T\u2010cells 1 (NFATc1), dendritic cell\u2010specific transmembrane protein (DC\u2010STAMP), TRAP, and cathepsin K in RANKL\u2010stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8\/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8\/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8\/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8\/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.<\/jats:p>","DOI":"10.1002\/jcp.28321","type":"journal-article","created":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T05:05:21Z","timestamp":1550811921000},"page":"16503-16516","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Cyclin\u2010dependent kinase 8\/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing"],"prefix":"10.1002","volume":"234","author":[{"given":"Mehdi","family":"Amirhosseini","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine Faculty of Medicine and Health Sciences, Link\u00f6ping University Link\u00f6ping 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