机械前交叉韧带损伤后小鼠创伤后骨关节炎发展的结构、功能和蛋白质组学性别差异

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage Pub Date : 2025-05-16 DOI:10.1016/j.joca.2025.05.004

Emily M Van Zeeland,Brandon Kassel,Travis Montoya,Anthony J Saviola,Lindsey H Burton,Jeremiah T Easley,Brad B Nelson,Kelly S Santangelo,Katie J Sikes

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引用次数: 0

摘要

目的创伤后骨关节炎（pta）的发生与性别有关。本研究旨在通过纵向活动能力评估、x线影像、组织学评估和非靶向蛋白质组学，全面表征前交叉韧带（ACL）损伤后雄性和雌性小鼠PTOA的发展。设计：在12周龄时，110只C57BL6J小鼠（雄性70只，雌性70只）接受单侧机械性前交叉韧带断裂，以诱发上眦胬肉。30只小鼠（雄性15只，雌性15只）作为naïve对照。通过自愿笼监测、步态分析和静态负重，在伤后56天内每周评估上睑下垂发展的症状。通过纵向x线片和多个终点的组织病理学来评估pta病理。在损伤后3、7和14天，以完整的ACL作为对照，使用非靶向无标记蛋白定量分析ACL蛋白质组。结果损伤后，与雌性相比，雄性小鼠的整体活动明显减少，包括头部移动距离减少（56天的平均差异：-3.81[95%CI:-7.45至-0.18]）。雄性表现出较宽的后肢姿态（平均差值56d: 0.28[95%CI:0.01 ~ 0.56]）和持续的后肢卸载（平均差值56d: 0.30[95%CI:0.08 ~ 0.52]）。纵向x线分析显示无明显的性别差异。组织学评估显示，男性的关节病理更严重（平均差异56天：49.97[95%CI:5.78 ~ 94.15]）。女性也表现出强烈的蛋白质组反应，在第3天达到峰值，与炎症、凝血级联和雌激素信号有关。结论：本研究揭示了雄性小鼠PTOA的进展增加，表现为活动障碍、组织学评分恶化和蛋白质组反应分化。这些见解将促进未来对pta预防治疗策略的研究。

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Structural, functional, and proteomic based sex differences in murine post-traumatic osteoarthritis development following mechanical anterior cruciate ligament injury.

OBJECTIVE Post-traumatic osteoarthritis (PTOA) is known to be influenced by sex. This study aimed to comprehensively characterize PTOA development in male and female mice following anterior cruciate ligament (ACL) injury through longitudinal mobility assessments, radiographic imaging, histologic evaluation, and untargeted proteomics. DESIGN At 12 weeks of age, 110 C57BL6J mice (70 males, 70 females) underwent unilateral mechanical ACL rupture to induce PTOA. 30 mice (15 males, 15 females) served as naïve controls. Symptoms of PTOA development were assessed weekly for 56-days post-injury through voluntary cage monitoring, gait analysis, and static weight bearing. PTOA pathology was evaluated through longitudinal radiographs and histopathology at multiple endpoints. ACL proteomes were analyzed using untargeted label-free protein quantification at 3-, 7-, and 14-days post-injury, with intact ACLs serving as controls. RESULTS Post-injury, male mice showed significant reductions in overall activity compared to females, including decreased head distance traveled (mean difference 56d: -3.81[95%CI:-7.45 to -0.18]). Males exhibited wider hindlimb stance (mean difference 56d: 0.28[95%CI:0.01 to 0.56]) and persistent hindlimb offloading (mean difference 56d: 0.30[95%CI:0.08 to 0.52]). Longitudinal radiographic analysis revealed no significant sex-based differences. Histological assessments revealed more severe joint pathology in males (mean difference 56d: 49.97[95%CI:5.78 to 94.15]). Females also demonstrated a robust proteomic response peaking at 3-days, with notable pathways related to inflammation, the coagulation cascade, and estrogen signaling. CONCLUSION This study revealed increased progression of PTOA in male mice evidenced by mobility impairments, worsened histologic scores, and divergent proteomic responses. These insights will enhance future research on therapeutic strategies for PTOA prevention.

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来源期刊

Osteoarthritis and Cartilage 医学-风湿病学

CiteScore

11.70

自引率

7.10%

发文量

802

审稿时长

52 days

期刊介绍： Osteoarthritis and Cartilage is the official journal of the Osteoarthritis Research Society International. It is an international, multidisciplinary journal that disseminates information for the many kinds of specialists and practitioners concerned with osteoarthritis.