Open AccessSexual Dimorphism in MAPK-Activated Protein Kinase-2 (MK2) Regulation of RANKL-Induced Osteoclastogenesis in Osteoclast Progenitor Subpopulations
Author(s) -
Bethany A. Herbert,
Michael S. Valerio,
Matthias Gaestel,
Keith L. Kirkwood
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0125387
Subject(s) - rankl , osteoclast , biology , endocrinology , mapk/erk pathway , medicine , signal transduction , microbiology and biotechnology , tartrate resistant acid phosphatase , progenitor cell , chemistry , activator (genetics) , receptor , stem cell , biochemistry
Osteoclasts (OCs) are bone-resorptive cells critical for maintaining skeletal integrity through coupled bone turnover. OC differentiation and activation requires receptor activator of NF-kB ligand (RANKL) signaling through the p38 MAPK pathway. However the role of the p38 MAPK substrate, MAPK-activated protein kinase 2 (MK2), is not clearly delineated. Within the bone marrow exists a specific subpopulation of defined osteoclast progenitor cells (dOCPs) with surface expression of B220 - Gr1 - CD11b lo/- CD115 + (dOCP lo/- ). In this study, we isolated dOCPs from male and female mice to determine sex-specific effects of MK2 signaling in osteoclastogenesis (OCgen). Male Mk2 -/- mice display an increase in the dOCP lo cell population when compared to Mk2 +/+ mice, while female Mk2 -/- and Mk2 +/+ mice exhibit no difference. Defined OCPs from male and female Mk2 +/+ and Mk2 -/- bone marrow were treated with macrophage colony stimulation factor (M-CSF) and RANKL cytokines to promote OCgen. RANKL treatment of dOCP lo cells stimulated p38 and MK2 phosphorylation. Tartrate-resistant acid phosphatase (TRAP) assays were used to quantify OC number, size, and TRAP enzyme activity post-RANKL stimulation. MK2 signaling was critical for male dOCP lo OCgen, yet MK2 signaling regulated OCgen from female dOCP - and CD11b hi subpopulations as well. The functional gene, Ctsk , was attenuated in both male and female Mk2 -/- dOCP lo -derived OCs. Conversely, MK2 signaling was only critical for gene expression of pre-OC fusion genes, Oc-stamp and Tm7sf4 , in male OCgen. Therefore, these data suggest there is a sexual dimorphism in MK2 signaling of OCP subpopulations.