Sexual Dimorphism in MAPK-Activated Protein Kinase-2 (MK2) Regulation of RANKL-Induced Osteoclastogenesis in Osteoclast Progenitor Subpopulations

• Published in: PloS one Vol. 10; no. 5; p. e0125387
• Main Authors: Herbert, Bethany A, Valerio, Michael S, Gaestel, Matthias, Kirkwood, Keith L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.05.2015; Public Library of Science (PLoS)
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid Phosphatase - metabolism; Acid resistance; Animals; Arthritis; Biochemistry; Biocompatibility; Biological research; Bone marrow; Bone Marrow Cells; Bone turnover; Cathepsin K - genetics; CD11b antigen; Cell cycle; Cell Differentiation; Cells (biology); Cells, Cultured; Cytokines; Dimorphism (Biology); Disease; Enzymatic activity; Enzyme activity; Female; Females; Gender differences; Gene expression; Gene fusion; Health sciences; Inflammation; Intracellular Signaling Peptides and Proteins - metabolism; Isoenzymes - metabolism; Kinases; Ligands (Biochemistry); Macrophage colony-stimulating factor; Macrophages; Male; MAP kinase; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-activated protein kinases; NF-κB protein; NFATC Transcription Factors - metabolism; Oral hygiene; Osteoclastogenesis; Osteoclasts; Osteoclasts (Biology); Osteoclasts - cytology; Osteoclasts - metabolism; Osteoprogenitor cells; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Physiological aspects; Physiology; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Proteins; RANK Ligand - metabolism; Rodents; Sex Characteristics; Sexual dimorphism; Signal Transduction; Signaling; Stem Cells - cytology; Stimulation; Subpopulations; Substrates; Tartrate-Resistant Acid Phosphatase; TRANCE protein; Transcription factors; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125387

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.