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-CD11blo/-CD115+ (dOCPlo/-). 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 dOCPlo 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 dOCPlo 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 dOCPlo OCgen, yet MK2 signaling regulated OCgen from female dOCP- and CD11bhi subpopulations as well. The functional gene, Ctsk, was attenuated in both male and female Mk2-/- dOCPlo-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.
Highlights
Osteoclasts (OCs) are multi-nucleated bone-resorbing cells that form by fusion of osteoclast progenitor cells (OCPs) arising from the hematopoietic cell lineage [1,2,3]
mitogen activated protein kinase (MAPK)-activated protein kinase 2 (MK2) deficiency led to a consistent decrease in formation of OCs derived from female defined osteoclast progenitor cells (dOCPs)- and CD11bhi cells on days 3 and 5 of receptor activator of NFkB ligand (RANKL) treatment (P 0.05, Fig 1A and 1B)
OCs derived from male Mk2-/- dOCPlo cells were reduced in number and size compared to Mk2+/+ OCs (P 0.05) by day 5 of RANKL differentiation (Fig 1A and 1C)
Summary
Osteoclasts (OCs) are multi-nucleated bone-resorbing cells that form by fusion of osteoclast progenitor cells (OCPs) arising from the hematopoietic cell lineage [1,2,3]. MK2 Is Needed for Osteoclastogenesis replaced by bone forming osteoblasts (known as coupled bone turnover) [4,5,6]. In pathological conditions such as periodontal disease, osteoporosis, and arthritis, over-activation of OCs leads to excessive resorption and bone deterioration [7, 8]. Sexual dimorphisms exist in diseases associated with inflammation and bone loss. Post-menopausal women have decreased bone integrity and biomechanical strength than men [9]. Men are at higher risk than women for periodontal disease, an oral disease characterized by inflammation and bone resorption [10]. One study provided evidence that estrogen replacement therapy is protective in women with periodontal disease [11]. OCs are the essential cell type involved directly in metabolic and pathological bone loss syndromes in both males and females
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