Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture
Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture
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DOI：
10.1172/jci8195
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发表时间：
2000-03-01
影响因子：
15.9
通讯作者：
Pilbeam, CC
中科院分区：
文献类型：
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作者：
Okada, Y;Lorenzo, JA;Pilbeam, CC
我们研究了破坏前列腺素G/H合酶基因PGHS-1和PGHS-2对破骨细胞形成的影响。与野生型（PGHS-2（+/+））培养物相比，缺乏PGHS-2（PGHS-2（-/-））的小鼠骨髓培养物中前列腺素E-2（PGE（2））的产生显著减少。无论是由1，25-二羟维生素D-3（1，25-D）还是由甲状旁腺激素（PTH）刺激，PGHS-2（-/-）培养物中的破骨细胞形成相对于野生型培养物减少了60-70%，这种作用可以通过提供外源性PGE逆转（2）。杂合子小鼠的培养物显示中等反应。PGHS抑制剂在野生型培养物中引起破骨细胞形成的类似下降。共培养实验表明，支持成骨细胞，而不是破骨细胞的前体，占钝响应1，25-D和PTH。这种反应的缺乏似乎是成骨细胞中RANK配体（RANKL）表达减少的结果。我们用外源性RANKL培养脾细胞，发现PGHS-2（-/-）中破骨细胞形成比野生型培养物低50%，显然是因为前者细胞表达高水平的GM-CSF。在野生型小鼠而非PGHS-2（-/-）小鼠的颅盖骨上方注射PTH可引起高钙血症。5周龄PGHS-2（-/-）小鼠的骨组织学检查未发现异常。缺乏PGHS-1的小鼠在所有这些参数上与野生型小鼠相似。这些数据表明，PGHS-2是不必要的野生型骨发育，但发挥了关键作用，在骨吸收刺激1，25-D和PTH。
We examined the effect on osteoclast formation of disrupting the prostaglandin G/H synthase genes PGHS-1 and-2. Prostaglandin E-2 (PGE(2)) production was significantly reduced in marrow cultures from mice lacking PGHS-2 (PGHS-2(-/-)) compared with wild-type (PGHS-2(+/+)) cultures. Osteoclast formation, whether stimulated by 1,25-dihydroxyvitamin D-3 (1,25-D) or by parathyroid hormone (PTH), was reduced by 60-70% in PGHS-2(-/-) cultures relative to wild-type cultures, an effect that could be reversed by providing exogenous PGE(2). Cultures from heterozygous mice showed an intermediate response. PGHS inhibitors caused a similar drop in osteoclast formation in wild-type cultures. Coculture experiments showed that supporting osteoblasts, rather than osteoclast precursors, accounted for the blunted response to 1,25-D and PTH. This lack of response appeared to result from reduced expression of RANK ligand (RANKL) in osteoblasts. We cultured spleen cells with exogenous RANKL and found that osteoclast formation was 50% lower in PGHS-2(-/-) than in wild-type cultures, apparently because the former cells expressed high levels of GM-CSF. Injection of PTH above the calvaria caused hypercalcemia in wild-type but not PGHS-2(-/-) mice. Histological examination of bone from 5-week-old PGHS-2(-/-) mice revealed no abnormalities. Mice lacking PGHS-1 were similar to wild-type mice in all of these parameters. These data suggest that PGHS-2 is not necessary for wild-type bone development but plays a critical role in bone resorption stimulated by 1,25-D and PTH.