Löwik C W, Nibbering P H, van de Ruit M, Papapoulos S E
Department of Endocrinology, University Hospital Leiden, The Netherlands.
J Clin Invest. 1994 Apr;93(4):1465-72. doi: 10.1172/JCI117124.
Nitric oxide (NO) has been suggested to be involved in the regulation of osteoclast activity. Since osteoblasts, through the release of various factors, are the main regulators of osteoclastic resorption, first we have investigated whether osteoblast-like cells and fetal mouse long bone explants are able to produce NO. Second, we have assessed the effect of NO on osteoclastic resorption in whole bone cultures. In this study we show that primary rat osteoblast-like cells as well as the clonal rat osteoblast-like cell line UMR-106, stimulated with IFN-gamma together with TNF-alpha and LPS, produce NO, measured as nitrite production. IL-1 alpha enhanced while TGF-beta 2 inhibited TNF-alpha + IFN-gamma + LPS-stimulated NO production in UMR-106 cells dose dependently. Both the cytokines, however, had no effect when given alone. The competitive inhibitor of NO production, NG-monomethyl-arginine (L-NMMA), and cycloheximide abolished the increase in nitrite production induced by TNF-alpha + IFN-gamma + LPS, while hydrocortisone had no effect, as previously reported for chondrocytes. Calciotropic hormones had either no effect [1,25(OH)2D3] or had a small inhibitory effect (parathyroid hormone) on stimulated NO production. Furthermore, we found that in cultured fetal mouse long bone explants the combination of TNF-alpha + IFN-gamma + LPS as well as the NO donor sodium nitroprusside could inhibit osteoclastic resorption, measured as 45Ca release. The inhibition of resorption was prevented by concurrent administration of L-NMMA. Histological evaluation revealed that the TNF-alpha + IFN-gamma + LPS-induced inhibition of 45Ca release was associated with a decrease in the number of tartrate-resistant acid phosphatase-positive osteoclasts. We propose that the NO production by osteogenic cells (osteoblasts and chondrocytes) may represent an important regulatory mechanism of osteoclastic activity especially under pathological conditions characterized by release of bone-resorbing inflammatory cytokines.
一氧化氮（NO）已被认为参与破骨细胞活性的调节。由于成骨细胞通过释放各种因子，是破骨细胞吸收的主要调节因子，因此我们首先研究了成骨样细胞和胎鼠长骨外植体是否能够产生NO。其次，我们评估了NO对全骨培养中破骨细胞吸收的影响。在本研究中，我们表明，用γ干扰素、肿瘤坏死因子-α（TNF-α）和脂多糖（LPS）刺激的原代大鼠成骨样细胞以及克隆大鼠成骨样细胞系UMR-106，可产生以亚硝酸盐生成量衡量的NO。白细胞介素-1α（IL-1α）增强而转化生长因子-β2（TGF-β2）剂量依赖性地抑制UMR-106细胞中TNF-α +γ干扰素+ LPS刺激的NO生成。然而，这两种细胞因子单独使用时均无作用。NO生成的竞争性抑制剂Nω-单甲基精氨酸（L-NMMA）和环己酰亚胺消除了TNF-α +γ干扰素+ LPS诱导的亚硝酸盐生成增加，而氢化可的松则无作用，这与先前对软骨细胞的报道一致。钙调节激素对刺激的NO生成要么无作用[1,25-二羟维生素D3]，要么有轻微抑制作用（甲状旁腺激素）。此外，我们发现，在培养的胎鼠长骨外植体中，TNF-α +γ干扰素+ LPS以及NO供体硝普钠可抑制以45钙释放量衡量的破骨细胞吸收。同时给予L-NMMA可阻止吸收的抑制。组织学评估显示，TNF-α +γ干扰素+ LPS诱导的45钙释放抑制与抗酒石酸酸性磷酸酶阳性破骨细胞数量减少有关。我们认为，成骨细胞（成骨细胞和软骨细胞）产生的NO可能代表破骨细胞活性的一种重要调节机制，尤其是在以骨吸收性炎性细胞因子释放为特征的病理条件下。
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