Nair S P, Meghji S, Wilson M, Reddi K, White P, Henderson B
Maxillofacial Surgery Research Unit, Eastman Dental Insitute, University College London, United Kingdom.
Infect Immun. 1996 Jul;64(7):2371-80. doi: 10.1128/iai.64.7.2371-2380.1996.
Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities.
正常的骨重塑需要成骨细胞和破骨细胞谱系的生成与活性的协调调节。对这些整合的细胞系统的任何干扰都可能导致重塑失调，进而导致骨基质丢失。细菌是牙周炎、牙囊肿、细菌性关节炎和骨髓炎等常见病症中骨病理的重要原因。现在已经确定，许多与骨疾病相关的细菌含有或产生对骨细胞有强大作用的分子。其中一些分子，如革兰氏阳性细胞壁的成分（脂磷壁酸），在体外是骨吸收的弱刺激剂，而其他分子（PMT、cpn60）与最活跃的哺乳动物溶骨因子如细胞因子IL-1和TNF一样活跃。骨细胞谱系发育整合的复杂性意味着，许多知名的骨调节分子如甲状旁腺激素的作用机制仍存在疑问。对于目前已认识到的细菌骨调节分子，必须提出的关键问题如下：（i）它们与哪些细胞群体结合，（ii）受体及受体后事件的性质是什么，以及（iii）它们的作用是直接的还是依赖于次级细胞外骨调节因子如细胞因子、类花生酸等的诱导。就脂多糖而言，这种普遍存在的革兰氏阴性聚合物可能通过CD14受体与骨中的成骨细胞或其他细胞结合，并刺激它们释放细胞因子和类花生酸，进而诱导破骨细胞的募集和活化。这就解释了非甾体和抗细胞因子药物对脂多糖诱导的骨吸收的抑制作用。然而，其他细菌因子如强效毒素PMT可能通过阻断成骨细胞谱系的正常成熟途径起作用，从而在骨基质吸收和替代的严格调节过程中诱导失调。目前，尚无法确定细菌促进骨基质丢失的一般机制。许多细菌都能够刺激骨基质丢失，现有信息表明，每种生物体都拥有以不同方式与骨相互作用的不同因子。随着抗生素耐药性的迅速增加，尤其是金黄色葡萄球菌和结核分枝杆菌，这两种在两代人之前导致发达国家许多骨病理的生物体，我们敦促应更加关注细菌诱导的骨重塑问题，以便确定可能成为新治疗方式开发治疗靶点的发病机制。
