Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss

Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is...

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Main Authors:	Boyle, David L., Hammaker, Deepa, Edgar, Meghan, Zaiss, Mario M., Teufel, Stefan, David, Jean Pierre, Schett, Georg, Firestein, Gary S.
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882259/

id	pubmed-3882259
recordtype	oai_dc
spelling	pubmed-38822592014-01-07 Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss Boyle, David L. Hammaker, Deepa Edgar, Meghan Zaiss, Mario M. Teufel, Stefan David, Jean Pierre Schett, Georg Firestein, Gary S. Research Article Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3−/− cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3−/− and MKK6−/− mice by micro-CT analysis. Bone loss was partially inhibited in MKK3−/− as well as MKK6−/− mice, despite normal osteoclastogenesis in MKK6−/− cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation. Public Library of Science 2014-01-06 /pmc/articles/PMC3882259/ /pubmed/24400116 http://dx.doi.org/10.1371/journal.pone.0084818 Text en © 2014 Boyle et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Boyle, David L. Hammaker, Deepa Edgar, Meghan Zaiss, Mario M. Teufel, Stefan David, Jean Pierre Schett, Georg Firestein, Gary S.
spellingShingle	Boyle, David L. Hammaker, Deepa Edgar, Meghan Zaiss, Mario M. Teufel, Stefan David, Jean Pierre Schett, Georg Firestein, Gary S. Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
author_facet	Boyle, David L. Hammaker, Deepa Edgar, Meghan Zaiss, Mario M. Teufel, Stefan David, Jean Pierre Schett, Georg Firestein, Gary S.
author_sort	Boyle, David L.
title	Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
title_short	Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
title_full	Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
title_fullStr	Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
title_full_unstemmed	Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss
title_sort	differential roles of mapk kinases mkk3 and mkk6 in osteoclastogenesis and bone loss
description	Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38α is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3−/− cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3−/− and MKK6−/− mice by micro-CT analysis. Bone loss was partially inhibited in MKK3−/− as well as MKK6−/− mice, despite normal osteoclastogenesis in MKK6−/− cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882259/
_version_	1612044755033653248

Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss

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