Zou Wei, Bar-Shavit Zvi
The H. Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
J Bone Miner Res. 2002 Jul;17(7):1211-8. doi: 10.1359/jbmr.2002.17.7.1211.
Lipopolysaccharide (LPS) modulates bone resorption by augmentation of osteoclastogenesis. It increases in osteoblasts the production of RANKL, interleukin (IL)-1, prostaglandin E2 (PGE2), and TNF-alpha, each known to induce osteoclast activity, viability, and differentiation. We examined the role of direct interactions of LPS with osteoclast precursors in promoting their differentiation. To this end, we have used bone marrow mononuclear cell preparations in the absence of osteoblasts or stromal cells. We found that LPS does not induce osteoclast differentiation in these cells. Moreover, the inclusion of LPS blocked the osteoclastogenic activity of RANKL. However, LPS is a potent inducer of osteoclastogenesis in RANKL-pretreated cells, even if present in the absence of exogenous RANKL. Osteoprotegerin (OPG), does not affect the stimulatory phase of LPS modulation of osteoclastogenesis, ruling out involvement of endogenous RANKL. LPS induces the expression of TNF-a and IL-1beta in osteoclast precursors, regardless if they were or were not pretreated with RANKL. These two cytokines induced osteoclast differentiation in RANKL-pretreated cells. To examine if these cytokines mediate LPS effect in an autocrine mechanism, we measured the effect of their neutralization on LPS osteoclastogenic activity. Although neutralization of IL-1beta did not affect LPS activity, a marked inhibition was observed when TNF-alpha was neutralized. However, TNF-a expression was increased also in conditions in which LPS inhibited RANKL osteoclastogenic activity. We found that LPS reduces the expression of RANK and macrophage colony-stimulating factor (M-CSF) receptor. In summary, LPS impacts on osteoclastogenesis also via its interactions with the precursor cells. LPS inhibits RANKL activity by reducing the expression of RANK and M-CSF receptor and stimulates osteoclastogenesis in RANKL-pretreated cells via TNF-alpha.
脂多糖（LPS）通过增强破骨细胞生成来调节骨吸收。它可增加成骨细胞中核因子κB受体活化因子配体（RANKL）、白细胞介素（IL）-1、前列腺素E2（PGE2）和肿瘤坏死因子-α（TNF-α）的产生，这些物质均已知可诱导破骨细胞活性、生存能力及分化。我们研究了LPS与破骨细胞前体细胞直接相互作用在促进其分化中的作用。为此，我们使用了不存在成骨细胞或基质细胞的骨髓单个核细胞制剂。我们发现LPS不会在这些细胞中诱导破骨细胞分化。此外，加入LPS会阻断RANKL的破骨细胞生成活性。然而，LPS是RANKL预处理细胞中破骨细胞生成的有效诱导剂，即使在没有外源性RANKL的情况下也是如此。骨保护素（OPG）不影响LPS调节破骨细胞生成的刺激阶段，排除了内源性RANKL的参与。LPS可诱导破骨细胞前体细胞中TNF-α和IL-1β的表达，无论它们是否用RANKL预处理过。这两种细胞因子在RANKL预处理的细胞中诱导破骨细胞分化。为了研究这些细胞因子是否通过自分泌机制介导LPS的作用，我们测量了它们的中和对LPS破骨细胞生成活性的影响。虽然中和IL-1β不影响LPS活性，但中和TNF-α时观察到明显抑制。然而，在LPS抑制RANKL破骨细胞生成活性的情况下，TNF-α表达也会增加。我们发现LPS会降低RANK和巨噬细胞集落刺激因子（M-CSF）受体的表达。总之，LPS还通过与前体细胞的相互作用影响破骨细胞生成。LPS通过降低RANK和M-CSF受体的表达来抑制RANKL活性，并通过TNF-α刺激RANKL预处理细胞中的破骨细胞生成。
