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J Cell Biochem. 2013 Sep;114(9):2032-8. doi: 10.1002/jcb.24554.

SOCS-1/3 participation in FGF-2 signaling to modulate RANK ligand expression in paget's disease of bone.

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1
Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.

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.

KEYWORDS:

FGF-2; MEASLES VIRUS NUCLEOCAPSID PROTEIN (MVNP); PAGET's DISEASE OF BONE (PDB); RANK LIGAND (RANKL); SUPPRESSORS OF CYTOKINE SIGNALING (SOCS)

PMID:
23553658
DOI:
10.1002/jcb.24554
[Indexed for MEDLINE]
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