Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor
Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor
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DOI：
10.1172/jci119679
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
Teitelbaum, SL
中科院分区：
文献类型：
--
作者：
AbuAmer, Y;Ross, FP;Teitelbaum, SL
慢性骨感染，如牙周炎，常并发严重的骨质溶解。虽然LPS被认为是溶骨性病变发病机制的核心，但这种细菌衍生分子促进骨吸收的机制尚不清楚。我们发现，LPS诱导骨髓巨噬细胞（BMPs）表达c-src，我们证明是一个特定的破骨细胞表型的承诺的原癌基因产物。我们接下来转向LPS诱导的c-src的可能的可溶性介质。在测试的许多破骨细胞生成细胞因子中，只有TNF-α反映了LPS的c-src增强作用。提示LPS增强c-src是TNF介导的，内毒素依次诱导BMM表达TNF，然后是c-src。通过来自注射LPS的小鼠的培养的细菌的TNF和c-src表达，反映了暴露于循环内毒素的持续时间，表明内毒素在体内的作用也由TNF介导。（其拮抗TNF作用）减弱LPS对c-src的诱导。抗TNF抗体使c-src mRNA的LPS增强变黑，证实了细胞因子的体外调节作用，使用TNF受体缺失的小鼠的Bclad，我们证明了c-src的TNF诱导是通过细胞因子的p55而不是p75受体传递的。最重要的是，给予野生型小鼠的LPS促进破骨细胞前体分化，这通过离体培养的骨髓中的大量破骨细胞生成和体内大量表达破骨细胞标志物酒石酸盐抗性酸性磷酸酶的骨髓驻留细胞来证明。相反，LPS基本上不增强缺乏p55 TNF受体的小鼠中的破骨细胞增殖。证实了LPS诱导的破骨细胞生成在体内由TNF通过该受体介导。因此，靶向TNF和/或其p55受体的治疗本身作为预防慢性细菌感染的骨质溶解的手段。
Chronic bone infection, as attends periodontitis, is often complicated by severe osteolysis. While LPS is believed to be central to the pathogenesis of the osteolytic lesion, the mechanisms by which this bacteria-derived molecule promotes bone resorption are unknown. We find that LPS induces bone marrow macrophages (BMMs) to express c-src, a protooncogene product that we demonstrate is a specific marker of commitment to the osteoclast phenotype. We next turned to possible soluble mediators of LPS-induced c-src. Of a number of osteoclastogenic cytokines tested, only TNF-alpha mirrors the c-src-enhancing effect of LPS. Suggesting that LPS augmentation of c-src is TNF-mediated, endotoxin sequentially induces BMM expression of TNF, followed by c-src. TNF and c-src expression, by cultured BMMs derived from LPS-injected mice, reflects duration of exposure to circulating endotoxin, intimating that endotoxin's effect in vivo is also mediated by TNF, Consistent with these findings, thalidomide (which antagonizes TNF action) attenuates c-src induction by LPS, An anti-TNF antibody blacks LPS enhancement of c-src mRNA, validating the cytokine's modulating role in vitro, Using BMMs of TNF receptor-deleted mice, we demonstrate that TNF induction of c-src is transmitted through the cytokine's p55, but not p75, receptor. Most importantly, LPS administered to wild-type mice prompts osteoclast precursor differentiation, manifest by profound osteoclastogenesis in marrow cultured ex vivo, and by a profusion of marrow-residing cells expressing the osteoclast marker tartrate resistant acid phosphatase, in vivo, In contrast, LPS does not substantially enhance osteoclast proliferation in mice lacking the p55TNF receptor, confirming that LPS-induced osteoclastogenesis is mediated by TNF in vivo via this receptor, Thus, therapy targeting TNF and/or its p55 receptor presents itself as a means of preventing the osteolysis of chronic bacterial infection.