title: CXCL5 stimulation of RANK ligand expression in Paget's disease of bone.
abstract: Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (≈ 180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Real-time PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho-p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB.
authors: Charles P Darby Children's Research Institute, Charleston, SC 29425, USA.
authors: Kumaran
authors: K
authors: Sundaram
authors: D Sudhaker
authors: DS
authors: Rao
authors: William L
authors: WL
authors: Ries
authors: Sakamuri V
authors: SV
authors: Reddy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D054365:Chemokine CXCL5 / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008875:Middle Aged; D010001:Osteitis Deformans / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D050882:CREB-Binding Protein