title: Sexual Dimorphism in MAPK-Activated Protein Kinase-2 (MK2) Regulation of RANKL-Induced Osteoclastogenesis in Osteoclast Progenitor Subpopulations.
abstract: 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 andTm7sf4, in male OCgen. Therefore, these data suggest there is a sexual dimorphism in MK2 signaling of OCP subpopulations.
authors.affiliation: Department of Oral Health Sciences and the Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Herbert
authors.affiliation: Department of Oral Health Sciences and the Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Valerio
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Department of Oral Health Sciences and the Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D056657:Cathepsin K / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D000071681:Tartrate-Resistant Acid Phosphatase; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000135:Acid Phosphatase; D056657:Cathepsin K; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D017346:Protein Serine-Threonine Kinases; D053245:RANK Ligand; D000071681:Tartrate-Resistant Acid Phosphatase; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C494005:Nfatc1 protein, mouse; C505689:Tnfsf11 protein, mouse; C000605511:Acp5 protein, mouse; C534132:Ctsk protein, mouse