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Open AccessArticle

Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases

1
Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN 55455, USA
2
Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN 55455, USA
3
Department of Developmental and Surgical Sciences, University of Minnesota School of Dentistry, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 1056; https://doi.org/10.3390/ijms21031056
Received: 9 January 2020 / Revised: 1 February 2020 / Accepted: 4 February 2020 / Published: 5 February 2020
(This article belongs to the Section Molecular Immunology)
Balanced osteoclast and osteoblast activity is necessary for skeletal health, whereas unbalanced osteoclast activity causes bone loss in many skeletal conditions. A better understanding of pathways that regulate osteoclast differentiation and activity is necessary for the development of new therapies to better manage bone resorption. The roles of Protein Kinase D (PKD) family of serine/threonine kinases in osteoclasts have not been well characterized. In this study we use immunofluorescence analysis to reveal that PKD2 and PKD3, the isoforms expressed in osteoclasts, are found in the nucleus and cytoplasm, the mitotic spindle and midbody, and in association with the actin belt. We show that PKD inhibitors CRT0066101 and CID755673 inhibit several distinct aspects of osteoclast formation. Treating bone marrow macrophages with lower doses of the PKD inhibitors had little effect on M-CSF + RANKL-dependent induction into committed osteoclast precursors, but inhibited their motility and subsequent differentiation into multinucleated mature osteoclasts, whereas higher doses of the PKD inhibitors induced apoptosis of the preosteoclasts. Treating post-fusion multinucleated osteoclasts with the inhibitors disrupted the osteoclast actin belts and impaired their resorptive activity. In conclusion, these data implicate PKD kinases as positive regulators of osteoclasts, which are essential for multiple distinct processes throughout their formation and function. View Full-Text
Keywords: osteoclasts; protein kinase D; cellular differentiation; actin cytoskeleton; bone resorption osteoclasts; protein kinase D; cellular differentiation; actin cytoskeleton; bone resorption
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Leightner, A.C.; Mello Guimaraes Meyers, C.; Evans, M.D.; Mansky, K.C.; Gopalakrishnan, R.; Jensen, E.D. Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases. Int. J. Mol. Sci. 2020, 21, 1056.

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