title: Soluble glucocorticoid-induced tumor necrosis factor receptor stimulates osteoclastogenesis by down-regulation of osteoprotegerin in bone marrow stromal cells.
abstract: Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR) is a potent stimulator of osteoclastogenesis. The mechanism by which it induces osteoclastogenesis was studied by culturing bone-marrow-derived macrophages (BMM) with conditioned medium from mouse bone marrow stromal cells. GITR and GITR ligand (GITRL) were expressed on the surface of bone marrow stromal cells, and sGITR-induced osteoclastogenesis was inhibited by anti-GITRL Ab, indicating that stimulatory effect of osteoclastogenesis by sGITR involved signaling via GITRL. Bone marrow stromal cells up-regulated cyclooxygenase-2 (COX-2) and produced prostaglandin E(2) (PGE(2)) early in their response to sGITR, and the stimulation of osteoclastogenesis was markedly inhibited by NS398, a COX-2 inhibitor. Later, sGITR markedly reduced the steady-state level of osteoprotegerin (OPG) mRNA and increased receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA. NS398 blocked the sGITR-induced reduction of OPG mRNA but did not significantly affect the sGITR-induced rise in RANKL mRNA. This suggests that down-regulation of OPG by PGE(2) is involved in sGITR-induced osteoclast (OC) formation in the presence of conditioned medium from mouse bone marrow stromal cells.
authors.affiliation: Department of Biological Sciences and the Immunomodulation Research Center, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Shin
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kang
authors.forename: Dong-Sul
authors.initials: DS
authors.lastname: Lee
authors.forename: Hye-Seon
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D053450:Glucocorticoid-Induced TNFR-Related Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000502:physiology
chemical_list: D000906:Antibodies; D052246:Cyclooxygenase 2 Inhibitors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053244:Osteoprotegerin; D011458:Prostaglandins E; D053245:RANK Ligand; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D051546:Cyclooxygenase 2