Elevated serum kininogen in patients with Paget's disease of bone: a role in marrow stromal/preosteoblast cell proliferation.
Paget's disease (PD) of bone is a chronic focal skeletal disorder characterized by excessive bone resorption followed by abundant new bone formation. Enhanced levels of IL-6, RANKL, M-CSF, and endothelin-1 have been associated with PD. In the present study, we identified increased serum levels (2 to 5-fold) of inflammatory cytokine, kininogen (KNG) in patients with PD compared to normal subjects. Treatment of pagetic bone marrow derived stromal/preosteoblast cells with recombinant KNG (25 ng/ml) for 24 h period resulted in a 5-fold increase in the levels of phospho-HSP27 and a 3-fold increase in ERK1/2 phosphorylation in these cells. However, pagetic stromal cells stimulated with KNG in the presence of ERK activation inhibitor peptide did not significantly affect the levels of phospho-HSP27. KNG increased normal and pagetic marrow stromal cell proliferation at 1.4-fold and 2.5-fold, respectively. KNG in the presence of an ERK inhibitor peptide did not stimulate pagetic marrow stromal cell proliferation. Furthermore, siRNA suppression of HSP27 expression significantly decreased KNG inhibition of etoposide-induced caspase-3 activation and apoptosis in these cells. In summary, KNG modulate bone marrow derived stromal/preosteoblast cell proliferation and suppress etoposide-induced apoptosis through ERK and HSP27 activation, respectively. These results implicate a pathophysiologic role for KNG in patients with PD.
Tsuruga
Eichi
E
Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
Rao
D Sudhaker
DS
Baatz
John E
JE
Reddy
Sakamuri V
SV
D017209:Apoptosis; D001854:Bone Marrow Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007704:Kininogens / Q000097:blood* / Q000494:pharmacology*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D010001:Osteitis Deformans / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007704:Kininogens; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases