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1.
J Pharm Pharmacol ; 62(8): 985-94, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20663032

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 Distribution
3.
J Bone Miner Res ; 21(11): 1704-12, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17002560

ABSTRACT

UNLABELLED: We examined OVX-induced bone loss in three TLD mouse models. In TLD mice, OVX caused trabecular bone loss equivalent to that of WT. In contrast, cortical bone loss with OVX was variable. We conclude that T lymphocytes do not influence OVX-induced trabecular bone loss. INTRODUCTION: We examined ovariectomy (OVX)-induced bone loss in three T lymphocyte-deficient (TLD) mouse models: nude mice, recombination activating gene 2-deficient (RAG2 KO) mice, and T cell receptor alpha chain-deficient (TCRalpha KO) mice. MATERIALS AND METHODS: Bone mass was examined by DXA, microCT, and histomorphometry. We also examined the effect of OVX on T lymphocytes in the bone marrow and spleens of wildtype (WT) mice and on in vitro osteoclastogenesis and colony forming unit-granulocyte macrophage (CFU-GM) activity in the bone marrow of WT and nude mice. RESULTS: In WT mice, OVX did not alter T lymphocyte number in the bone marrow but did increase T lymphocytes in the spleen. Comparison of bone mass in nude, RAG2 KO, and TCRalpha KO mice with WT as measured by DXA showed decreased femoral bone mass in nude mice and increased vertebral bone mass in RAG2 KO mice. In TCRalpha KO mice, femoral, tibial, and vertebral bone mass were decreased. In vertebrae and long bones, bone loss with OVX was consistently present in WT mice but variably present in TLD mice as measured by DXA. In contrast, microCT and histomorphometry showed similar trabecular bone loss after OVX in all mice. However, femoral cortical bone loss occurred only in WT and RAG2 KO mice. OVX produced similar trabecular bone loss in WT and TCRalpha KO mice and also induced cortical bone loss in both. Histomorphometry showed that TRACP(+) area in bones was increased by OVX in femurs from both WT and nude mice as was in vitro osteoclast-like cell formation and CFU-GM activity. CONCLUSIONS: These results show that OVX caused similar trabecular bone loss in both WT and TLD mice. The ability of DXA and measurement of cortical bone loss to show OVX-induced effects on bone mass was variable. It seems that T lymphocytes are not critical for OVX-induced trabecular bone loss in these mouse models.


Subject(s)
Bone and Bones/physiology , Ovariectomy/methods , T-Lymphocytes/physiology , Animals , Bone Marrow Cells/metabolism , Bone and Bones/metabolism , Female , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Osteoclasts/metabolism , Recombination, Genetic , Stem Cells/metabolism , T-Lymphocytes/metabolism
4.
J Exp Med ; 202(5): 589-95, 2005 Sep 05.
Article in English | MEDLINE | ID: mdl-16147974

ABSTRACT

Osteoclasts are derived from myeloid lineage cells, and their differentiation is supported by various osteotropic factors, including the tumor necrosis factor (TNF) family member TNF-related activation-induced cytokine (TRANCE). Genetic deletion of TRANCE or its receptor, receptor activator of nuclear factor kappaB (RANK), results in severely osteopetrotic mice with no osteoclasts in their bones. TNF receptor-associated factor (TRAF) 6 is a key signaling adaptor for RANK, and its deficiency leads to similar osteopetrosis. Hence, the current paradigm holds that TRANCE-RANK interaction and subsequent signaling via TRAF6 are essential for the generation of functional osteoclasts. Surprisingly, we show that hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can become osteoclasts in vitro when they are stimulated with TNF-alpha in the presence of cofactors such as TGF-beta. We provide direct evidence against the current paradigm that the TRANCE-RANK-TRAF6 pathway is essential for osteoclast differentiation and suggest the potential existence of alternative routes for osteoclast differentiation.


Subject(s)
Cell Differentiation/drug effects , Hematopoietic Stem Cells/drug effects , Osteoclasts/cytology , Osteoclasts/metabolism , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Carrier Proteins/genetics , DNA Primers , Gene Deletion , Histological Techniques , Lymphotoxin-alpha/pharmacology , Male , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Reverse Transcriptase Polymerase Chain Reaction , TNF Receptor-Associated Factor 6/deficiency , TNF Receptor-Associated Factor 6/genetics
5.
EMBO Rep ; 6(2): 171-6, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15678156

ABSTRACT

TRANCE/TRAF6 signalling governs osteoclastogenesis in vivo. Only the TRANCE receptor (TRANCE-R) has been shown to induce osteoclastogenesis, even though other immune receptors, including CD40 and IL-1R/Toll-like receptor, use TRAF6 to activate overlapping signalling cascades. These observations led us to question whether qualitative or quantitative differences exist between the TRAF6-mediated signals induced by TRANCE and by other ligand-receptor pairs. Here we show that stimulation by overexpressed wild-type CD40 can induce osteoclastogenesis. Stimulation through modified CD40 containing increased numbers of TRAF6-binding sites in the cytoplasmic tails showed a dose-dependent increase in the activation of p38 kinase and more pronounced osteoclastogenesis. Moreover, precursors overexpressing TRAF6 differentiate into osteoclasts in the absence of additional signals from TRANCE. Our results suggest that differences in the osteoclastogenesis-inducing capacity of TRANCE-R versus other TRAF6-associated receptors may in part stem from a quantitative difference in the TRAF6-mediated signals.


Subject(s)
Osteoclasts/metabolism , Signal Transduction/physiology , TNF Receptor-Associated Factor 6/metabolism , Animals , CD40 Antigens/metabolism , Cell Differentiation/physiology , Humans , Osteoclasts/cytology , Receptor Activator of Nuclear Factor-kappa B , Receptors, Tumor Necrosis Factor/metabolism
6.
Arthritis Rheum ; 48(12): 3538-41, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14674006

ABSTRACT

We describe the case of a 44-year-old Japanese woman with severe nodular erythematous skin lesions and arthritis mutilans who was admitted for further treatment of multicentric reticulohistiocytosis. Skin and synovial biopsies showed heavy infiltration with tartrate-resistant acid phosphatase-positive histiocytes and multinucleated giant cells. Immunohistochemical analysis showed that some of the mononuclear cells in the skin were positive for RANKL. After 1 month of Alendronate, an aminobisphosphonate, given at a dosage of 10 mg once a week intravenously for the first 6 weeks and then once a month thereafter, the arthritis and skin nodules improved, and the remission has continued for more than 2 years. The findings in this patient suggest that osteoclast-like multinucleated giant cells differentiate locally in the skin from infiltrating histiocytes with the help of RANKL-positive stromal cells and that alendronate acts directly on cells of monocyte/macrophage lineage in humans. Thus, alendronate should be added to the list of drugs for the treatment of multicentric reticulohistiocytosis.


Subject(s)
Alendronate/therapeutic use , Histiocytes/drug effects , Histiocytosis, Non-Langerhans-Cell/drug therapy , Histiocytosis, Non-Langerhans-Cell/pathology , Adult , Arthritis/drug therapy , Arthritis/pathology , Female , Histiocytes/pathology , Humans , Skin Diseases/drug therapy , Skin Diseases/pathology
7.
Clin Calcium ; 12(8): 1157-64, 2002 Aug.
Article in Japanese | MEDLINE | ID: mdl-15775414

ABSTRACT

Osteoclastogenesis inhibitory factor (OCIF) was isolated from the conditioned medium of human embryonic lung fibroblasts. OCIF is a novel member of the tumor necrosis factor receptor superfamily and identical with Osteoprotegerin (OPG) discovered by the Amgen researchers. Consequently, through the identification of receptor activator of NF-kappaB ligand (RANKL) as a target molecule of OCIF/OPG, it was demonstrated that RANKL is a crucial factor in the differentiation, maturation, and activation of osteoclasts. Discovery of OCIF/OPG and RANKL has broken new ground in the field of bone physiopathology. Moreover, OCIF/OPG not only contributes to the field of basic science but also is anticipated as a novel therapeutic candidate for the treatment of primary and secondary osteoporosis through a series of pre-clinical and clinical studies. Because OCIF/OPG and RANKL have been proven to be involved in the onset and development of many metabolic bone diseases besides osteoporosis, OCIF/OPG is also expected as a therapeutic candidate for the treatment of such bone diseases.

8.
J Biol Chem ; 277(8): 6631-6, 2002 Feb 22.
Article in English | MEDLINE | ID: mdl-11733492

ABSTRACT

Bone remodeling involves the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts. Receptor activator of NF-kappa B ligand (RANKL, also known as ODF and OPGL), a member of the tumor necrosis factor (TNF) family, triggers osteoclastogenesis by forming a complex with its receptor, RANK. We have determined the crystal structure of the extracellular domain of mouse RANKL at 2.2-A resolution. The structure reveals that the RANKL extracellular domain is trimeric, which was also shown by analytical ultracentrifugation, and each subunit has a beta-strand jellyroll topology like the other members of the TNF family. A comparison of RANKL with TNF beta and TNF-related apoptosis-inducing ligand (TRAIL), whose structures were determined to be in the complex form with their respective receptor, reveals conserved and specific features of RANKL in the TNF superfamily and suggests the presence of key residues of RANKL for receptor binding.


Subject(s)
Carrier Proteins/chemistry , Membrane Glycoproteins/chemistry , Amino Acid Sequence , Animals , Bone Remodeling , Carrier Proteins/metabolism , Crystallography, X-Ray , Glycoproteins/metabolism , Humans , Lymphotoxin-alpha/chemistry , Macromolecular Substances , Membrane Glycoproteins/metabolism , Mice , Models, Molecular , Molecular Sequence Data , NF-kappa B/metabolism , Osteoclasts/cytology , Osteoprotegerin , Peptide Fragments/chemistry , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Tumor Necrosis Factor , Recombinant Fusion Proteins/chemistry , Sensitivity and Specificity , Sequence Alignment , Sequence Homology, Amino Acid
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