title: SOCS-1/3 participation in FGF-2 signaling to modulate RANK ligand expression in paget's disease of bone.
abstract: Paget's disease of bone (PDB) is a chronic focal skeletal disorder characterized by excessive bone resorption followed by disorganized new bone formation. Measles virus nucleocapsid (MVNP) is implicated in pathogenesis of PDB. RANK ligand (RANKL), a critical osteoclastogenic factor expressed on bone marrow stromal/preosteoblast cells is upregulated in PDB. We recently demonstrated that fibroblast growth factor-2 (FGF-2) which induces RANKL expression is elevated in PDB. In this study, we hypothesized that FGF-2 modulates suppressors of cytokine signaling (SOCS) to induce RANKL expression in PDB. We identified increased levels of SOCS-1/3 mRNA expression in bone marrow mononuclear cells derived from patients with PDB compared to normal subjects. Interestingly, conditioned media obtained from MVNP transduced osteoclast progenitor cells significantly increased SOCS-1/3 mRNA expression in stromal/preosteoblast cells. We next examined if SOCS participates in FGF-2 signaling to modulate RANKL gene expression. We showed that FGF-2 stimulation significantly increased SOCS-1/3 expression in human bone marrow stromal/preosteoblast cells. In addition, co-expression of SOCS-1/3 with hRANKL gene promoter-luciferase reporter plasmid in marrow stromal cells demonstrated a significant increase in promoter activity without FGF-2 stimulation. Furthermore, siRNA inhibition of STAT-1 suppresses FGF-2 increased SOCS-1/3 expression in these cells. Thus, our results suggest that SOCS participates in FGF-2 modulation of RANKL expression in PDB.
authors.affiliation: Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Sundaram
authors.forename: Joseph
authors.initials: J
authors.lastname: Senn
authors.forename: Sakamuri V
authors.initials: SV
authors.lastname: Reddy
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008459:Measles virus / Q000378:metabolism; D019590:Nucleocapsid Proteins / Q000235:genetics / Q000378:metabolism; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019590:Nucleocapsid Proteins; D053245:RANK Ligand; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016222:Fibroblast Growth Factor 2
keywords: FGF-2; MEASLES VIRUS NUCLEOCAPSID PROTEIN (MVNP); PAGET's DISEASE OF BONE (PDB); RANK LIGAND (RANKL); SUPPRESSORS OF CYTOKINE SIGNALING (SOCS)