BACKGROUND Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA. METHODS Skeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR). RESULTS MSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages. CONCLUSIONS This therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.

中文翻译：

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创伤后骨关节炎的滑膜炎症，结构病理和疼痛之间的关系：干细胞和透明质酸治疗的差异作用。

背景技术滑膜炎与骨关节炎（OA）的疼痛和结构病理的严重程度和进展有关。OA滑膜中有炎症或免疫细胞亚群（包括巨噬细胞和淋巴细胞）增加的报道，但是具体亚群如何影响有症状或结构性OA疾病的进展尚不清楚。透明质酸（HA）和间充质干细胞（MSC）这两种疗法已在某些临床环境中显示出功效：HA充当改善关节功能并减轻疼痛的装置，而MSC可能具有免疫调节和改善疾病的作用。我们使用这些药物来调查创伤后OA中疼痛敏感性或结构损伤的改变是否与滑膜炎症反应的调节有关。方法骨骼成熟的C57BL6雄性小鼠接受内侧-半月板不稳定（DMM）手术，然后关节内注射盐水，透明质酸十六烷基酰胺衍生物（Hymovis），骨髓衍生干细胞（MSCs）或MSC + Hymovis。我们量化了与OA相关的软骨，软骨下骨和滑膜组织病理学以及相关的疼痛敏感性（触觉性异常性疼痛）的进展。滑膜淋巴细胞，单核细胞/巨噬细胞及其亚群通过荧光激活细胞分选术（FACS）进行定量，关键炎症介质和分解代谢酶基因的表达通过实时聚合酶链反应（PCR）进行定量。结果MSC而非Hymovis显着降低了晚期（DMM后12周）软骨蛋白聚糖损失和结构损伤。两种疗法最初都可以减轻痛觉异常，但是Hymovis可以在8周和12周时使痛觉异常明显改善。MSC的软骨保护作用与滑膜炎性细胞群体的特定变化无关，而与损伤后滑膜Adamts4，Adamts5，Mmp3和Mmp9表达的调节有关。所有治疗均降低了急性损伤后异常性疼痛，同时滑膜巨噬细胞和T细胞数量减少，而对Hymovis的疼痛致敏作用的长期影响与M2c巨噬细胞增加有关。结论这项在小鼠中的治疗研究表明，软骨，骨骼或滑膜（组织）病理学与疼痛敏感性之间的相关性较差。特定的滑膜炎性细胞亚群的变化可能与慢性OA疼痛致敏有关，是对症治疗的新目标。