Department of Orthopaedics University Medical Centre Utrecht, Rm G05.228, P.O. Box 85500, Utrecht 3508 GA, the Netherlands. j.alblas @umcutrecht.nl.
Eur Cell Mater. 2019 May 16;37:402-419. doi: 10.22203/eCM.v037a24.
Immune cells and their soluble factors regulate skeletal cells during normal bone regeneration and pathological bone formation. Bacterial infections can trigger immune responses that activate pro-osteogenic pathways, but these are usually overshadowed by osteolysis and concerns of systemic inflammation. The aim of this study was to determine whether the transient local inflammatory reaction to non-viable bacterial immune agonists could lead to favourable new bone formation. In a series of rabbit studies, as proof-of-concept, how tibial intramedullary injection of viable or killed bacterial species affected bone remodelling and new bone formation was determined. Application of killed bacteria led to considerable new bone formation after 4 weeks, without the prolonged systemic inflammation and exaggerated bone lysis seen with active infection. The osteo-immunomodulatory effects of various species of killed bacteria and the dose response relationship were subsequently screened in ectopically-implanted ceramic scaffolds. Histomorphometry after 8 weeks showed that a relatively low dose of killed bacteria enhanced ectopic bone induction. Moreover, lipoteichoic acid - the bacterial cell-wall derived toll-like-receptor (TLR)-2 activator - was identified as an osteo-stimulatory factor. Collectively, the data indicated that bacterial stimuli could be harnessed to stimulate osteogenesis, which occurs through a synergy with osteoinductive signals. This finding holds promise for the use of non-viable bacteria, bacterial antigens, or their simplified analogues as immuno-modulatory bone regenerating tools in bone biomaterials.
免疫细胞及其可溶性因子在骨骼正常再生和病理性骨形成过程中调节骨骼细胞。细菌感染会引发免疫反应，激活促成骨途径，但这些反应通常会被骨溶解和全身炎症反应所掩盖。本研究旨在确定非存活细菌免疫激动剂引起的短暂局部炎症反应是否会导致有利的新骨形成。在一系列兔研究中，作为概念验证，研究了活细菌或死细菌经胫骨髓内注射对骨重塑和新骨形成的影响。在 4 周后，应用死细菌可导致大量新骨形成，而不会出现持续的全身炎症和活跃感染时所见的骨溶解加剧。随后，在异位植入的陶瓷支架中筛选了各种死细菌的骨免疫调节作用及其剂量反应关系。8 周后的组织形态计量学显示，相对低剂量的死细菌增强了异位骨诱导。此外，发现细菌细胞壁衍生的 TLR-2 激活剂——脂磷壁酸是一种促骨形成因子。总之，这些数据表明可以利用细菌刺激物来刺激成骨作用，这种作用是通过与成骨信号协同产生的。这一发现为非存活细菌、细菌抗原或其简化类似物作为骨生物材料中免疫调节骨再生工具的应用提供了希望。
