Department of Veterinary and Animal Science, University of Copenhagen, Frederiksberg C, Denmark; Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
J Comp Pathol. 2020 Aug;179:7-24. doi: 10.1016/j.jcpa.2020.06.010. Epub 2020 Aug 8.
Bone loss is a major complication of osteomyelitis and from numerous in-vitro studies, it has been concluded that the bone lysis is caused by elevated expression of the receptor activator of nuclear factor κB ligand (RANKL), leading to increased osteoclast activity. However, we failed to find any relationship between bone loss and osseous RANKL expression in a porcine model of acute and chronic implant-associated osteomyelitis (IAO) due to Staphylococcus aureus or in chronic osteomyelitis lesions in slaughter pigs. Surprisingly, we found that the expression of RANKL was reduced during chronic bone infections. This is in line with the few studies conducted on human samples. A significant bone loss was observed in IAO lesions and in lesions from slaughter pigs, but with no indication of osteoclast involvement using histochemistry, immunohistochemistry for RANKL, receptor activator of nuclear factor kappa-B, osteoprotegerin and cathepsin K, and high-throughput quantitative real-time polymerase chain reaction on bone tissue from osteomyelitic lesions. A strong inflammatory response was seen in the infected animals and, therefore, we propose proteolytic enzymes induced by inflammation to be a major component of the bone loss. Furthermore, we found a significant upregulation of the IL26 gene in infected animals, which can inhibit RANKL-induced osteoclastogenesis, but has no homologue in mice. This finding emphasises that neither murine models nor in-vitro studies can mirror human disease development completely. The present study emphasises that the interactions between microorganisms, the immune system and bone cells in osteomyelitis are too complex to be accurately represented by an in-vitro model.
骨丢失是骨髓炎的主要并发症，大量体外研究表明，骨溶解是由于核因子κB 受体激活剂配体（RANKL）表达升高引起的，导致破骨细胞活性增加。然而，我们未能在金黄色葡萄球菌引起的急性和慢性植入物相关骨髓炎（IAO）的猪模型或屠宰猪的慢性骨髓炎病变中发现骨丢失与骨 RANKL 表达之间存在任何关系。令人惊讶的是，我们发现 RANKL 的表达在慢性骨感染期间减少。这与对人类样本进行的少数研究一致。IAO 病变和屠宰猪病变中观察到明显的骨丢失，但组织化学、RANKL、核因子κB 受体激活剂、骨保护素和组织蛋白酶 K 的免疫组织化学以及骨组织高通量实时聚合酶链反应均未显示破骨细胞参与。感染动物中存在强烈的炎症反应，因此，我们提出炎症诱导的蛋白水解酶是骨丢失的主要成分。此外，我们发现感染动物中 IL26 基因显著上调，该基因可抑制 RANKL 诱导的破骨细胞生成，但在小鼠中没有同源物。这一发现强调了，无论是小鼠模型还是体外研究都不能完全反映人类疾病的发展。本研究强调，骨髓炎中微生物、免疫系统和骨细胞之间的相互作用过于复杂，无法通过体外模型准确表示。
