Bradykinin potentiates cytokine-induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression.
Författare och institution:
Anna Bernhold Brechter (-); Ulf H Lerner (Institutionen för medicin, avdelningen för invärtesmedicin)
Arthritis and rheumatism, 56 ( 3 ) s. 910-23
Artikel, refereegranskad vetenskaplig
OBJECTIVE: Bradykinin (BK) stimulates bone resorption in vitro and synergistically potentiates interleukin-1 (IL-1)-induced bone resorption and prostaglandin (PG) formation, suggesting that kinins are important in inflammation-induced bone loss. The present study was undertaken to study 1) the role of the kinin B1 and B2 receptors in the synergistic interaction with IL-1 and tumor necrosis factor alpha (TNFalpha), 2) the molecular mechanisms involved in synergistic enhancement of PG formation, and 3) the effects of kinins on cytokine-induced expression of RANKL, RANK, and osteoprotegerin (OPG) (the latter being crucial molecules in osteoclast differentiation). METHODS: Formation of PGs, expression of enzymes involved in arachidonic acid metabolism, and expression of RANKL, RANK, and OPG were assessed in the human osteoblastic cell line MG-63 and in mouse calvarial bones. The role of NF-kappaB and MAP kinases was studied using pharmacologic inhibitors. RESULTS: PGE(2) formation and cyclooxygenase 2 (COX-2) protein expression were induced by IL-1beta and potentiated by kinins with affinity for the B1 or B2 receptors, resulting in PGE(2)-dependent enhancement of RANKL. The enhancements of PGE(2) formation and COX-2 were markedly decreased by inhibition of p38 and JNK MAP kinases, whereas inhibition of NF-kappaB resulted in abolishment of the PGE(2) response with only slight inhibition of COX-2. CONCLUSION: Kinin B1 and B2 receptors synergistically potentiate IL-1- and TNFalpha-induced PG biosynthesis in osteoblasts by a mechanism involving increased levels of COX-2, resulting in increased RANKL. The synergistic stimulation is dependent on NF-kappaB and MAP kinases. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including that in rheumatoid arthritis.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin ->
Animals, Bradykinin, physiology, Cell Line, Tumor, Cells, Cultured, Cyclooxygenase 2, genetics, metabolism, Cytokines, physiology, Dinoprostone, biosynthesis, Humans, Interleukin-1beta, physiology, Mice, Mice, Inbred Strains, Mitogen-Activated Protein Kinase Kinases, physiology, NF-kappa B, physiology, Osteoblasts, metabolism, Osteoprotegerin, genetics, metabolism, RANK Ligand, genetics, metabolism, RNA, Messenger, metabolism, Receptor Activator of Nuclear Factor-kappa B, genetics, metabolism, Receptor, Bradykinin B1, physiology, Receptor, Bradykinin B2, physiology, Tumor Necrosis Factor-alpha, physiology
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