Objective

To determine whether osteoarthritis (OA) pain characteristics and mechanistic pathways in pre-clinical models are phenotype-specific.

Design

Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA), vs sham-surgery/immunised-controls (Sham/Im-CT). Pain behaviour (allodynia, mechanical- and thermal-hyperalgesia, hindlimb static weight-bearing, stride-length) and lumbar dorsal root ganglia (DRG) gene-expression were measured at baseline, day-3, week-1/-2/-4/-8/-16, and pain-behaviour:gene-expression:joint-pathology associations investigated.

Results

DMM and AIA induced structural OA defined by progressively increasing cartilage erosion, subchondral bone sclerosis and osteophyte size and maturation. All pain-behaviours were modified, with model-specific differences in severity and temporal pattern. Tactile allodynia developed acutely in both models and persisted to week-16. During early-OA (wk4-8) there was; reduced right hindlimb weight-bearing in AIA; thermal-hyperalgesia and reduced stride-length in DMM. During chronic-OA (wk12-16); mechanical-hyperalgesia and reduced right hindlimb weight-bearing were observed in DMM only. There were no associations in either model between different pain-behaviour outcomes. A coordinated DRG-expression profile was observed in sham and Im-CT for all 11 genes tested, but not in AIA and DMM. At wk-16 despite equivalent joint pathology, changes in DRG-expression (Calca, Trpa1, Trpv1, Trpv4) were observed only in DMM. In AIA mechanical-hyperalgesia was associated with Trpv1 (r = −0.79) and Il1b (r = 0.53). In DMM stride-length was associated with Calca, Tac1, Trpv1, Trpv2, Trpv4 and Adamts5 (r = 0.4–0.57). DRG gene-expression change was correlated with subchondral-bone sclerosis in DMM, and cartilage damage in AIA. Positive pain-behaviour:joint-pathology associations were only present in AIA - for synovitis, subchondral-bone resorption, chondrocyte-hypertrophy and cartilage damage.

Conclusion

Pain and peripheral sensory neuronal responses are OA-phenotype-specific with distinct pathology:pain-outcome:molecular-mechanism relationships.

中文翻译：

---

不同骨关节炎动物模型表型中的病理与疼痛关系：测量内容、测量时间以及测量方式很重要

 客观的

确定临床前模型中骨关节炎 (OA) 疼痛特征和机制途径是否具有表型特异性。

 设计

与假手术/免疫对照 (Sham/Im-CT) 相比，11 周龄雄性 C57BL6 小鼠患有单侧内侧半月板不稳定 (DMM) 或抗原诱导关节炎 (AIA)。在基线、第 3 天、第 1/-2/- 周测量疼痛行为（异常性疼痛、机械和热痛觉过敏、后肢静态负重、步长）和腰椎背根神经节 (DRG) 基因表达4/-8/-16，并研究了疼痛行为：基因表达：关节病理学关联。

 结果

DMM 和 AIA 诱导结构性 OA，其定义为逐渐增加的软骨侵蚀、软骨下骨硬化以及骨赘大小和成熟。所有疼痛行为都经过修改，在严重程度和时间模式上存在模型特定的差异。两种模型均出现严重的触觉异常性疼痛，并持续至第 16 周。在早期 OA 期间（第 4-8 周）有： AIA 右后肢负重减少； DMM 中的热痛觉过敏和步幅缩短。慢性 OA 期间（第 12-16 周）；仅在 DMM 中观察到机械痛觉过敏和右后肢负重减少。在这两种模型中，不同的疼痛行为结果之间都没有关联。在假手术和 Im-CT 中观察到所有 11 个测试基因的协调 DRG 表达谱，但在 AIA 和 DMM 中没有观察到。在第 16 周，尽管关节病理学相同，但仅在 DMM 中观察到 DRG 表达（ Calca、Trpa1、Trpv1、Trpv4 ）的变化。在 AIA 中，机械痛觉过敏与Trpv1 ( r = -0.79) 和Il1b ( r = 0.53) 相关。在 DMM 中，步长与Calca、Tac1、Trpv1、Trpv2、Trpv4和Adamts5相关（ r = 0.4–0.57）。 DRG 基因表达变化与 DMM 中的软骨下骨硬化以及 AIA 中的软骨损伤相关。积极的疼痛行为：关节病理关联仅存在于 AIA 中——滑膜炎、软骨下骨吸收、软骨细胞肥大和软骨损伤。

 结论

疼痛和周围感觉神经元反应是 OA 表型特异性的，具有不同的病理学：疼痛结果：分子机制关系。