Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA.
Connect Tissue Res. 2024 Jan;65(1):26-40. doi: 10.1080/03008207.2023.2269257. Epub 2024 Feb 1.
PURPOSE/AIM: Cartilage injury and subsequent osteoarthritis (OA) are debilitating conditions affecting millions worldwide. As there are no cures for these ailments, novel therapies are needed to suppress disease pathogenesis. Given that joint injuries are known to produce damage-associated molecular patterns (DAMPs), our central premise is that the Toll-like receptor 4 (TLR4) pathway is a principal driver in the early response to cartilage damage and subsequent pathology. We postulate that TLR4 activation is initiated/perpetuated by DAMPs released following joint damage. Thus, antagonism of the TLR4 pathway immediately after injury may suppress the development of joint surface defects.
Two groups were utilized: (1) 8-week-old, male C57BL6 mice treated systemically with a known TLR4 antagonist and (2) mice injected with vehicle control. A full-depth cartilage lesion on the midline of the patellofemoral groove was created in the right knee of each mouse. The left knee was used as a sham surgery control. Gait changes were evaluated over 4 weeks using a quantitative gait analysis system. At harvest, knee joints were processed for pathologic assessment, Nanostring® transcript expression, and immunohistochemistry (IHC).
Short-term treatment with a TLR4 antagonist at 14-days significantly improved relevant gait parameters; improved cartilage metrics and modified Mankin scores were also seen. Additionally, mRNA expression and IHC showed reduced expression of inflammatory mediators in animals treated with the TLR4 antagonist.
Collectively, this work demonstrates that systemic treatment with a TLR4 antagonist is protective to further cartilage damage 14-days post-injury in a murine model of induced disease.
目的/目标：软骨损伤和随后的骨关节炎（OA）是影响全球数百万人的衰弱性疾病。由于这些疾病没有治愈方法，因此需要新的疗法来抑制疾病的发病机制。鉴于关节损伤已知会产生损伤相关分子模式（DAMP），我们的核心前提是 Toll 样受体 4（TLR4）途径是对软骨损伤和随后的病理学的早期反应的主要驱动因素。我们假设 TLR4 的激活是由关节损伤后释放的 DAMPs 引发/维持的。因此，在损伤后立即拮抗 TLR4 途径可能会抑制关节表面缺陷的发展。
使用了两组：（1）用已知的 TLR4 拮抗剂全身性治疗的 8 周龄雄性 C57BL6 小鼠，（2）注射载体对照的小鼠。在每只小鼠的髌股沟中线处造成全层软骨损伤。左侧膝关节用作假手术对照。使用定量步态分析系统在 4 周内评估步态变化。收获时，对膝关节进行病理评估、Nanostring®转录物表达和免疫组织化学（IHC）处理。
TLR4 拮抗剂在 14 天时的短期治疗显著改善了相关的步态参数；也观察到软骨指标和改良的 Mankin 评分得到改善。此外，在接受 TLR4 拮抗剂治疗的动物中，mRNA 表达和 IHC 显示炎症介质的表达减少。
总的来说，这项工作表明，在诱导疾病的小鼠模型中，TLR4 拮抗剂的全身治疗在损伤后 14 天对进一步的软骨损伤具有保护作用。
