ABSTRACT
OBJECTIVES: Our aim was to investigate the effect of PEGylation on the uptake of osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) into rat liver, kidney and spleen, and human liver. METHODS: Copolymer of polyethyleneglycol allylmethylether and maleamic acid sodium salt with OCIF (poly(PEG)-OCIF) (0.5 mg/kg) was administered to rats and the concentrations of poly(PEG)-OCIF in the liver, kidney and spleen at 15 min after administration were measured by ELISA. For human liver uptake, the liver perfusion of OCIF and (3)H-labelled poly(PEG)-OCIF was conducted using fresh human liver block. KEY FINDINGS: The tissue uptake of poly(PEG)-OCIF in rats was significantly lower compared with that of OCIF. In fresh human liver perfusion, (3)H-poly(PEG)-OCIF was rarely taken up into the liver. On the other hand, more than 50% of the perfused OCIF was taken up. CONCLUSIONS: PEGylation of OCIF using poly(PEG) dramatically suppressed the uptake of OCIF into human liver as well as into rat liver and could be a promising approach for improving the pharmacokinetic and pharmacological effects of OCIF in the clinical setting.
Subject(s)
Bone Density Conservation Agents/pharmacokinetics , Liver/metabolism , Osteoprotegerin/pharmacokinetics , Polyethylene Glycols/chemistry , Animals , Biological Transport , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/blood , Bone Density Conservation Agents/chemistry , Cells, Cultured , Chemistry, Pharmaceutical , Down-Regulation , Enzyme-Linked Immunosorbent Assay , Female , Heparin/metabolism , Humans , Injections, Intravenous , Kidney/metabolism , Maleates/chemistry , Mice , Osteoclasts/drug effects , Osteoprotegerin/administration & dosage , Osteoprotegerin/blood , Osteoprotegerin/chemistry , Ovariectomy , Perfusion , Rats , Rats, Sprague-Dawley , Spleen/metabolism , Tissue DistributionABSTRACT
Osteoclastogenesis inhibitory factor (OCIF) is a novel member of the Tumor Necrosis Factor Receptor superfamily and identical with Osteoprotegerin (OPG) discovered by Amgen researchers. OCIF/OPG is a decoy receptor (a soluble receptor that acts as an antagonist) that binds to osteoblast cells via Receptor Activator of NF-kappa B Ligand (RANKL) involved in the signal transduction between osteoblast cells and osteoclastic progenitor cells, eventually suppressing differentiation of the progenitor cells into osteoclasts. The balance between the OCIF/OPG and RANKL is regulated by cytokines and hormones. Studies on OCIF/OPG-RANKL system have provided important insights into the pathogenesis of human metabolic bone diseases, leading to the expectation of OCIF/OPG as a novel candidate for a therapeutic agent for metabolic bone diseases.
Subject(s)
Glycoproteins , Osteoporosis/drug therapy , Receptors, Cytoplasmic and Nuclear , Animals , Bone and Bones/metabolism , Carrier Proteins/physiology , Cell Differentiation/genetics , Clinical Trials as Topic , Drug Design , Glycoproteins/chemistry , Glycoproteins/physiology , Glycoproteins/therapeutic use , Humans , Membrane Glycoproteins/physiology , Osteoblasts , Osteoclasts/cytology , Osteoporosis/etiology , Osteoprotegerin , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/physiology , Receptors, Cytoplasmic and Nuclear/therapeutic use , Receptors, Tumor Necrosis Factor , Signal Transduction/geneticsABSTRACT
As the magnetic field of widely used MR scanners is one of the strongest magnetic fields to which people are exposed, the biological influence of the static magnetic field of MR scanners is of great concern. One magnetic interaction in biological subjects is the magnetic torque on the magnetic moment induced by biomagnetic substances. The red blood cell is a major biomagnetic substance, and the blood flow may be influenced by the magnetic field. However, the underlying mechanisms have been poorly understood. To examine the mechanisms of the magnetic influence on blood viscosity, we measured the time for blood to fall through a glass capillary inside and outside a 1.5 T MR scanner. Our in vitro results showed that the blood viscosity significantly increased in a 1.5 T MR scanner, and also clarified the mechanism of the interaction between red blood cells and the external magnetic field. Notably, the blood viscosity increased depending on blood oxygenation and the shear rate of the blood flow. Thus, our findings suggest that even a 1.5 T magnetic field may modulate blood flow.
