Objective

Synovial inflammation contributes to cartilage degeneration and osteoarthritis (OA) development. Targeting the inflammation process may provide a promising strategy for OA treatment. It has been demonstrated that C1q/tumour necrosis factor-related protein-9 (CTRP9) has immunosuppression capabilities. Thus, we conducted this study to investigate the role of CTRP9 in OA and its therapeutic potential.

Method

The expression level of CTRP9 was quantified in peripheral blood mononuclear cells (PBMCs), serum, and synovial cells (SCs) isolated from OA patients by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The relationship between the expression level of CTRP9 and the disease activity of OA was determined. The inflammation-suppressing effects of CTRP9 were assessed in vitro.

Results

The expression level of CTRP9 was increased in the PBMCs and serum of OA compared to healthy controls. The serum level of CTRP9 was found to be positively correlated with erythrocyte sedimentation rate, C-reactive protein, and visual analogue scale score. In addition, CTRP9 protein suppressed the expression of pro-inflammatory cytokines, including tumour necrosis factor-α, interleukin-6, and interleukin-1β, in PBMCs and SCs in vitro. CTRP9 was increased in OA patients and positively correlated with the disease activity. The recombinant CTRP9 had inflammation-suppressing activities in vitro.

Conclusion

CTRP9 may have therapeutic potential for treating OA. Osteoarthritis (OA) is characterized as cartilage destruction resulting from synovial inflammation (1–6 Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 2012;64:1697–707.
Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 2010;6:625–35.
Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol 2012;8:665–73.
Aigner T, Soder S, Gebhard PM, McAlinden A, Haag J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis--structure, chaos and senescence. Nat Clin Pract Rheumatol 2007;3:391–9.
Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007;213:626–34.
Vanhaverbeke T, Pardaens L, Wittoek R. Natural disease progression in finger osteoarthritis: results from a 10 year follow-up cohort. Scand J Rheumatol 2020;49:498–504. ). According to the clinical symptoms and levels of inflammation, OA has been divided into primary generalized osteoarthritis (PGOA) and erosive inflammatory osteoarthritis (EIOA) (7 Hamerman D. The biology of osteoarthritis. N Engl J Med 1989;320:1322–30.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). The only available treatment for OA is joint replacement. Thus, it is necessary to develop novel and effective therapeutic strategies to treat OA. Because synovial inflammation contributes to OA development, targeting the inflammation process may provide a promising strategy for OA treatment. Previous investigations showed that pro-inflammatory factors promoted OA development (8–10 de Lange-Brokaar BJ, Ioan-Facsinay A, Yusuf E, Visser AW, Kroon HM, Van Osch GJ, et al. Association of pain in knee osteoarthritis with distinct patterns of synovitis. Arthritis Rheumatol 2015;67:733–40.
Neogi T, Guermazi A, Roemer F, Nevitt MC, Scholz J, Arendt-Nielsen L, et al. Association of joint inflammation with pain sensitization in knee osteoarthritis: the multicenter osteoarthritis study. Arthritis Rheumatol 2016;68:654–61.
Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011;7:33–42. ), while anti-inflammatory factors suppressed it (11–14 de Lange-Brokaar BJ, Ioan-Facsinay A, Van Osch GJ, Zuurmond AM, Schoones J, Toes RE, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 2012;20:1484–99.
Silvestri T, Pulsatelli L, Dolzani P, Facchini A, Meliconi R. Elevated serum levels of soluble interleukin-4 receptor in osteoarthritis. Osteoarthritis Cartilage 2006;14:717–9.
van Meegeren ME, Roosendaal G, Jansen NW, Wenting MJ, van Wesel AC, van Roon JA, et al. IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage. Osteoarthritis Cartilage 2012;20:764–72.
Mussener A, Funa K, Kleinau S, Klareskog L. Dynamic expression of transforming growth factor-betas (TGF-beta) and their type I and type II receptors in the synovial tissue of arthritic rats. Clin Exp Immunol 1997;107:112–19. ). Thus, we conducted the present study to investigate the role of C1q/tumour necrosis factor-related protein-9 (CTRP9), an anti-inflammatory factor (15 Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Ge G, Spooner E, Hug C, et al. Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J 2009;23:241–58.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]), in OA, and its therapeutic potential.

中文翻译：

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C1q/TNF 相关蛋白 9 抑制骨关节炎患者滑膜细胞的炎症

客观的

滑膜炎症有助于软骨退化和骨关节炎 (OA) 的发展。针对炎症过程可能会为 OA 治疗提供有希望的策略。已证明 C1q/肿瘤坏死因子相关蛋白 9 (CTRP9) 具有免疫抑制能力。因此，我们进行了这项研究以研究 CTRP9 在 OA 中的作用及其治疗潜力。

方法

通过定量聚合酶链反应和酶联免疫吸附测定法对从 OA 患者分离的外周血单个核细胞 (PBMC)、血清和滑膜细胞 (SC) 中 CTRP9 的表达水平进行量化。确定了CTRP9的表达水平与OA疾病活动度之间的关系。CTRP9的炎症抑制作用在体外进行了评估。

结果

与健康对照相比，CTRP9 在 PBMC 和 OA 血清中的表达水平升高。发现CTRP9的血清水平与红细胞沉降率、C反应蛋白和视觉模拟量表评分呈正相关。此外，CTRP9 蛋白在体外抑制 PBMC 和 SCs 中促炎细胞因子的表达，包括肿瘤坏死因子-α、白细胞介素 6 和白细胞介素 1β。CTRP9 在 OA 患者中升高，并与疾病活动度呈正相关。重组CTRP9在体外具有抑制炎症的活性。

结论

CTRP9 可能具有治疗 OA 的治疗潜力。骨关节炎 (OA) 的特征是滑膜炎症导致的软骨破坏 ( 1-6 Loeser RF、Goldring SR、Scanzello CR、Goldring MB。 骨关节炎：关节作为器官的疾病。关节炎大黄2012；64：1697 – 707。
Sellam J，Berenbaum F. 滑膜炎在骨关节炎的病理生理学和临床症状中的作用。Nat Rev Rheumatol 2010；6：625 – 35。
伯尔DB，英勇MA。骨关节炎中的骨重塑. Nat Rev Rheumatol 2012；8：665 – 73。
Aigner T、Soder S、Gebhard PM、McAlinden A、Haag J。 _ 发病机制：软骨细胞在骨关节炎发病机制中的作用——结构、混乱和衰老。Nat Clin Prac Rheumatol 2007；3：391 – 9。
Goldring MB，Goldring SR。骨关节炎。细胞生理学杂志2007 ;213: 626 –34 .
Vanhaverbeke T , Pardaens L , Wittoek R . 手指骨关节炎的自然疾病进展：10 年随访队列的结果。Scand J Rheumatol 2020；49：498 – 504。 ）。根据临床症状和炎症程度，OA分为原发性全身性骨关节炎（PGOA）和糜烂性炎症性骨关节炎（EIOA）（7 哈默曼D. _ 骨关节炎的生物学。N Engl J Med 1989；320：1322 – 30。[Crossref]、[PubMed]、[Web of Science®]、 [Google Scholar]）。OA 唯一可用的治疗方法是关节置换。因此，有必要开发新的和有效的治疗策略来治疗 OA。由于滑膜炎症有助于 OA 的发展，因此针对炎症过程可能为 OA 治疗提供有希望的策略。先前的研究表明，促炎因子促进了 OA 的发展（8-10 de Lange-Brokaar BJ、Ioan-Facsinay A、Yusuf E、Visser AW、Kroon HM、Van Osch GJ等。膝关节骨性关节炎疼痛与滑膜炎不同类型的关联。关节炎风湿病2015 年；67：733 – 40。
Neogi T、Guermazi A、Roemer F、Nevitt MC、Scholz J、Arendt-Nielsen L等人。关节炎症与膝关节骨关节炎疼痛敏感性的关联：多中心骨关节炎研究。关节炎风湿病2016 年；68：654 – 61。
Kapoor M , Martel- Pelletier J , Lajeunesse D , Pelletier JP , Fahmi H. 促炎细胞因子在骨关节炎病理生理中的作用。Nat Rev Rheumatol 2011；7：33 – 42。 ），而抗炎因子抑制它（11-14 de Lange-Brokaar BJ、Ioan-Facsinay A、Van Osch GJ、Zuurmond AM、Schoones J、Toes RE等。骨关节炎中的滑膜炎症、免疫细胞及其细胞因子：综述。骨关节炎软骨2012；20：1484 – 99。
Silvestri T、Pulsatelli L、Dolzani P、Facchini A、Meliconi R。 _骨关节炎中可溶性白细胞介素 4 受体的血清水平升高。骨关节炎软骨2006 年；14：717 - 9。
van Meegeren ME、Roosendaal G、Jansen NW、Wenting MJ、van Wesel AC、van Roon JA等。单独使用 IL-4 和与 IL-10 联合使用可防止血液诱导的软骨损伤。骨关节炎软骨2012 年；20：764 – 72。
穆森纳_ _ _ _, Kleinau S , Klareskog L . 转化生长因子-β (TGF-β) 及其 I 型和 II 型受体在关节炎大鼠滑膜组织中的动态表达。临床实验免疫学1997 年；107: 112 – 19。 ）。因此，我们进行了本研究以调查 C1q/肿瘤坏死因子相关蛋白 9 (CTRP9) 的作用，这是一种抗炎因子 ( 15 Wong GW、Krawczyk SA、Kitidis-Mitrokostas C、Ge G、Spooner E、Hug C等。CTRP9 的鉴定和表征，一种新的分泌糖蛋白，来自脂肪组织，可降低小鼠的血清葡萄糖并与脂联素形成异源三聚体。FASEB J 2009；23：241 – 58。[Crossref]、[PubMed]、[Web of Science ®]  、[Google Scholar]），在 OA 及其治疗潜力。