Roper Philip M, Beetner Jessica, Davis Jennifer L, Shao Christine, Zhang Jason, Cox Linda, Pokhrel Nitin Kumar, Cassat James E, Rangel-Moreno Javier, Muthukrishnan Gowrishankar, Veis Deborah J
Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, Saint Louis, MO 63110, United States.
Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
JBMR Plus. 2025 May 19;9(9):ziaf093. doi: 10.1093/jbmrpl/ziaf093. eCollection 2025 Sep.
Osteoarticular infection, most commonly due to , can become chronic, leading to many complications including irreversible joint damage and osteomyelitis. Here, we established a hindlimb model of infection in young (6-wk-old) mice by introducing into the tibia through the knee joint, using methicillin-resistant clinical isolates (TI1-5) derived from children with osteomyelitis, and a skin isolate (NRS384), all of which were previously transduced with a modified operon to induce bioluminescence. Weekly in vivo bioluminescent imaging (BLI) revealed that all strains could establish a local infection in >90% of recipients at 1 wk post-inoculation. Most infections persisted throughout 4 wk, and those that cleared did so by week 2, although 2 strains, TI2 and TI5, had lower incidence at 2 wk and significantly lower progression. Histologic examination of BLI-positive limbs revealed primarily septic arthritis, with variable and less frequent osteomyelitis, with abscesses, bacterial microcolonies, and neutrophil infiltration in affected tissues. We also found osteoclasts and marrow fibrosis in many infected bones. Immunofluorescence demonstrated less intense neutrophil and T cell infiltration around infection sites for TI2, compared to the more aggressive TI1 and TI3 strains. Micro-CT revealed significantly reduced tibial trabecular bone volumes (BV/TV) from infected, BLI-positive legs compared to uninfected, BLI-negative legs, although the latter were lower than those from noninfected mice. There was significant negative correlation between BV/TV and BLI for all strains except TI5. Lastly, we tested pain behavioral responses of mice to the aggressive TI3 strain. Electronic von Frey and hot plate assessments showed altered nociception suggestive of pain over 4 wk. In sum, intratibial injection of causes persistent septic arthritis in young mice, with consistent differences between bacterial strains, allowing study of bacterial virulence and pathogenic host factors.
骨关节炎感染最常见的病因是……，可发展为慢性感染，导致许多并发症，包括不可逆转的关节损伤和骨髓炎。在此，我们通过将耐甲氧西林的……临床分离株（TI1 - 5）（源自患有骨髓炎的儿童）和一种皮肤分离株（NRS384）经膝关节引入幼龄（6周龄）小鼠的胫骨，建立了后肢感染模型，所有这些菌株先前都用改良的……操纵子进行了转导以诱导生物发光。每周进行的体内生物发光成像（BLI）显示，所有菌株在接种后1周时均可在>90%的受体中建立局部感染。大多数感染持续4周，那些清除的感染在第2周时清除，尽管有2个菌株TI2和TI5在第2周时发病率较低且进展明显较慢。对BLI阳性肢体的组织学检查主要显示为化脓性关节炎，骨髓炎的发生率各不相同且较低，受累组织中有脓肿、细菌微菌落和中性粒细胞浸润。我们还在许多受感染的骨骼中发现了破骨细胞和骨髓纤维化。免疫荧光显示，与侵袭性更强的TI1和TI3菌株相比，TI2感染部位周围的中性粒细胞和T细胞浸润强度较低。显微CT显示，与未感染、BLI阴性的腿部相比，感染、BLI阳性的腿部胫骨小梁骨体积（BV/TV）显著降低，尽管后者低于未感染小鼠的骨体积。除TI5外，所有菌株的BV/TV与BLI之间均存在显著负相关。最后，我们测试了小鼠对侵袭性TI3菌株的疼痛行为反应。电子von Frey和热板评估显示，在4周内伤害感受发生改变，提示存在疼痛。总之，经胫骨注射……可在幼龄小鼠中引起持续性化脓性关节炎，不同菌株之间存在一致差异，这有助于研究细菌毒力和致病性宿主因素。
