title: MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation.
abstract: Cytokine-directed osteoclastogenesis is initiated in response to macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) to drive formation of osteoclasts (OC), large bone resorptive cells of hematopoietic origin. RANKL-induced signaling activates the MAPK pathways, which initiates nuclear translocation of the master regulator of osteoclast formation, transcription factor NFATc1. Proper control over these signaling events is essential to normal OC formation response to stimuli. MAPK phosphatase 1 (MKP-1), a serine and tyrosine phosphatase encoded by the gene Dusp1, functions to dephosphorylate and subsequently inactivate MAPK (p38 and JNK) signaling essential in osteoclastogenesis. Here, we explored the role of MKP-1 during RANKL-driven osteoclastogenesis from defined (B220/CD45(-)GR1(-)CD11b(lo/-)CD115(+)) OC progenitor (dOCP) populations using WT and Dusp1(-/-) global knockout mice. Sorted cells were driven to OC by M-CSF pre-treatment followed by RANKL stimulation for 3days. OC formation and qPCR products were analyzed for maturation. Results indicate that Dusp1(-/-) dOCP form less numerous, significantly smaller and less functional OC compared to WT controls. These data were corroborated by mRNA expression of the key OC genes, Nfatc1 and Tm7sf4 (DC-STAMP), which were significantly reduced in early osteoclastogenesis in OC progenitor from Dusp1(-/-) mice. Intriguingly, our data reveals that MKP-1 may positively control OC formation in response to RANKL by regulating NFATc1 nuclear translocation. Collectively, this report supports the idea that MKP-1 signaling is essential in early osteoclastogenesis in response to RANKL-induced signaling.
authors.affiliation: Department of Craniofacial Biology, Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Valerio
authors.affiliation: Department of Craniofacial Biology, Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Herbert
authors.affiliation: Department of Craniofacial Biology, Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Griffin
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Department of Craniofacial Biology, Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Hill
authors.affiliation: Department of Craniofacial Biology, Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: klkirk@musc.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002459:Cell Fusion; D019070:Cell Lineage / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050778:NFATC Transcription Factors; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: Cytokine; MAPK phosphatase; Osteoclastogenesis; Progenitors; RANKL