Suppression of osteoprotegerin expression by prostaglandin E2 is crucially involved in lipopolysaccharide-induced osteoclast formation
Suppression of osteoprotegerin expression by prostaglandin E2 is crucially involved in lipopolysaccharide-induced osteoclast formation
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DOI：
10.4049/jimmunol.172.4.2504
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发表时间：
2004-02-15
影响因子：
4.4
通讯作者：
Nagai, K
中科院分区：
文献类型：
--
作者：
Suda, K;Udagawa, N;Nagai, K
LPS是炎性疾病中骨吸收的有效刺激物。在小鼠成骨细胞和骨髓细胞的共培养中研究了LPS诱导破骨细胞生成的机制。LPS刺激小鼠成骨细胞和骨髓细胞共培养中破骨细胞的形成和PGE（2）的产生，这种刺激作用可被环氧合酶-2抑制剂NS 398完全抑制。成骨细胞，而不是骨髓细胞，产生PGE（2）响应LPS。LPS诱导的破骨细胞形成也被骨保护素（OPG）抑制，骨保护素是NF-κ B配体受体激活剂（RANKL）的诱饵受体，但不被抗小鼠TNFR 1 Ab或IL-1受体拮抗剂抑制。LPS刺激成骨细胞RANKL mRNA表达，抑制OPG mRNA表达。NS 398可阻断LPS诱导的OPG mRNA表达下调，但不能阻断LPS诱导的RANKL mRNA表达上调，这表明PGE（2）对OPG表达的下调参与了共培养物中LPS诱导的破骨细胞形成。在含有OPG敲除小鼠来源的成骨细胞的共培养物中，NS 398未能抑制LPS诱导的破骨细胞生成。IL-1也刺激成骨细胞和破骨细胞形成的PGE 2的生产在共培养物中，和刺激被抑制NS 398。与LPS一样，NS 398不能抑制IL-1诱导的破骨细胞在与OPG缺陷型成骨细胞共培养中的形成。这些结果表明，IL-1和LPS通过两个平行事件刺激破骨细胞生成：直接增强RANKL表达和抑制OPG表达，后者由PGE（2）产生介导。免疫学杂志，2004，172：2504 - 2510.
LPS is a potent stimulator of bone resorption in inflammatory diseases. The mechanism by which LPS induces osteoclastogenesis was studied in cocultures of mouse osteoblasts and bone marrow cells. LPS stimulated osteoclast formation and PGE(2) production in cocultures of mouse osteoblasts and bone marrow cells, and the stimulation was completely inhibited by NS398, a cyclooxygenase-2 inhibitor. Osteoblasts, but not bone marrow cells, produced PGE(2) in response to LPS. LPS-induced osteoclast formation was also inhibited by osteoprotegerin (OPG), a decoy receptor of receptor activator of NF-kappaB ligand (RANKL), but not by anti-mouse TNFR1 Ab or IL-1 receptor antagonist. LPS induced both stimulation of RANKL mRNA expression and inhibition of OPG mRNA expression in osteoblasts. NS398 blocked LPS-induced down-regulation of OPG mRNA expression, but not LPS-induced up-regulation of RANKL mRNA expression, suggesting that down-regulation of OPG expression by PGE(2) is involved in LPS-induced osteoclast formation in the cocultures. NS398 failed to inhibit LPS-induced osteoclastogenesis in cocultures containing OPG knockout mouse-derived osteoblasts. IL-1 also stimulated PGE2 production in osteoblasts and osteoclast formation in the cocultures, and the stimulation was inhibited by NS398. As seen with LPS, NS398 failed to inhibit IL-1-induced osteoclast formation in cocultures with OPG-deficient osteoblasts. These results suggest that IL-1 as well as LPS stimulates osteoclastogenesis through two parallel events: direct enhancement of RANKL expression and suppression of OPG expression, which is mediated by PGE(2) production. The Journal of Immunology, 2004, 172: 2504 -2510.