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Crucial Involvement of the EP4 Subtype of Prostaglandin E Receptor in Osteoclast Formation by Proinflammatory Cytokines and Lipopolysaccharide
Author(s) -
Sakuma Yoko,
Tanaka Kiyoshi,
Suda Michio,
Yasoda Akihiro,
Natsui Koshi,
Tanaka Issei,
Ushikubi Fumitaka,
Narumiya Shuh,
Segi Eri,
Sugimoto Yukihiko,
Ichikawa Atsushi,
Nakao Kazuwa
Publication year - 2000
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2000.15.2.218
Subject(s) - osteoclast , prostaglandin e2 receptor , endocrinology , prostaglandin e2 , medicine , chemistry , proinflammatory cytokine , tumor necrosis factor alpha , receptor , agonist , biology , inflammation
Prostaglandin E 2 (PGE 2 ) exerts its effects through the PGE receptor that consists of four subtypes (EP1, EP2, EP3, and EP4). Osteoclast formation in the coculture of primary osteoblastic cells (POB) and bone marrow cells was enhanced more by 11‐deoxy‐PGE1 (an EP4 and EP2 agonist) than by butaprost (an EP2 agonist) and other agonists, which suggests that EP4 is the main factor in PGE 2 ‐induced osteoclast formation. PGE 2 ‐induced osteoclast formation was not observed in the coculture of POB from EP4‐deficient (EP4 k/o) mice and spleen cells from wild‐type (w/t) mice, whereas osteoclasts were formed in the coculture of POB from w/t mice and spleen cells from EP4‐k/o mice. In situ hybridization (ISH) showed that EP4 messenger RNA (mRNA) was expressed on osteoblastic cells but not on multinucleated cells (MNCs) in w/t mice. These results indicate that PGE 2 enhances osteoclast formation through its EP4 subtype on osteoblasts. Osteoclast formation by interleukin 1α (IL‐1α), tumor necrosis factor α (TNF‐α), basic fibroblast growth factor (bFGF), and lipopolysaccharide (LPS) was hardly observed in the coculture of POB and bone marrow cells, both from EP4‐k/o mice, which shows the crucial involvement of PG and the EP4 subtype in osteoclast formation by these molecules. In contrast, osteoclast formation by 1,25‐hydroxyvitamin D 3 (1,25(OH) 2 D 3 ) was not impaired and that by parathyroid hormone (PTH) was only partially impaired in EP4‐k/o mice, which may be related to the fact that EP4‐k/o mice revealed no gross skeletal abnormalities. Because it has been suggested that IL‐1α, TNF‐α, bFGF, and LPS are involved in inflammatory bone loss, our work can be expected to contribute to an understanding of the pathophysiology of these conditions.(J Bone Miner Res 2000;15:218–227)