Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing

Journal of Cellular Physiology
Mehdi AmirhosseiniAnna Fahlgren

Abstract

Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have 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-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in o...Continue Reading

References

Jul 1, 2004·Arthritis Research & Therapy·Lionel B Ivashkiv, Xiaoyu Hu
Jul 3, 2004·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Uma SankarMichael C Ostrowski
Mar 15, 2005·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Hiroshi TakatsunaKazuo Umezawa
Aug 9, 2005·Biochemical and Biophysical Research Communications·Oh Hyung KwonHyun-Jun Lee
Jul 7, 2007·Molecular Cell·Aaron Joseph DonnerJoaquin Maximiliano Espinosa
Feb 25, 2009·The Journal of Cell Biology·Toshihide MizoguchiNaoyuki Takahashi
Jan 12, 2010·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Kosuke TajimaYoshiaki Toyama
Mar 13, 2010·Journal of Cellular Biochemistry·Hyun-Ju KimSteven L Teitelbaum
Feb 18, 2011·Transcription·Matthew D GalbraithJoaquín M Espinosa
Dec 2, 2011·Methods in Molecular Biology·Astrid D Bakker, Jenneke Klein-Nulend
Aug 8, 2012·Proceedings of the National Academy of Sciences of the United States of America·Donald C PorterIgor B Roninson
Nov 28, 2012·Calcified Tissue International·José Luis Millán
Feb 8, 2013·Nature Medicine·Roland Baron, Michaela Kneissel
Mar 5, 2013·Cell Cycle·Weiting GuJun-Yuan Ji
May 7, 2013·Biochimica Et Biophysica Acta·Zsolt Szilagyi, Claes M Gustafsson
Oct 22, 2013·Biochimie·Josipa NemetMary Sopta
Oct 5, 2014·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Andreas HerchenhanMichael Kjaer
Oct 14, 2014·The Biochemical Journal·Erik HolmHarvey A Goldberg
Apr 2, 2015·Endocrinology and Metabolism·Brendan F BoyceZhenqiang Yao
May 27, 2015·Biochimica Et Biophysica Acta·Tomasz RzymskiKrzysztof Brzózka
May 29, 2015·Molecular Pharmacology·Mary E LawBrian K Law
Jun 29, 2015·Allergology International : Official Journal of the Japanese Society of Allergology·Kentaro IshiyamaChiharu Nishiyama
Jul 21, 2015·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Megan M WeivodaMerry Jo Oursler
May 12, 2016·Journal of Visualized Experiments : JoVE·Sarah R AmendKenneth J Pienta
Jun 5, 2016·Biochemical and Biophysical Research Communications·Ya YangChi Zhang
Aug 16, 2016·International Journal of Molecular Sciences·Minsuk KwonDaewon Jeong
Dec 15, 2016·Nature Communications·Bin HuangXiaochun Bai
Feb 18, 2017·Oncotarget·John Crown

❮ Previous
Next ❯

Citations

Apr 29, 2020·Doklady. Biochemistry and Biophysics·Y Y SilaevaA V Deykin
Sep 27, 2020·Annals of the New York Academy of Sciences·Jingjing ZhengLing Gao
Nov 10, 2020·Stem Cells and Development·Joseph StraubJamie J Newman
Dec 2, 2020·European Journal of Medicinal Chemistry·Dan WuXinhua Liu

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.