骨关节炎相关炎症应激对滑膜成纤维细胞力学响应的调节。

Modulation of the mechanical responses of synovial fibroblasts by osteoarthritis-associated inflammatory stressors.

机构信息

Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, United Kingdom.

Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, United Kingdom.

出版信息

Int J Biochem Cell Biol. 2020 Sep;126:105800. doi: 10.1016/j.biocel.2020.105800. Epub 2020 Jul 13.

DOI:10.1016/j.biocel.2020.105800

PMID:32673644

Abstract

OBJECTIVES

To compare mechanobiological response of synovial fibroblasts (SFb) from OA patient cohorts under mechanical load and inflammatory stressors for better understanding of SFb homeostatic functions.

METHODS

Primary SFb isolated from knee synovium of OA obese (OA-ob:SFb), OA-pre-obese (OA-Pob:SFb), non-OA arthroscopic (scope:SFb), and non-OA arthroscopic with cartilage damage (scope-CD:SFb) were exposed to OA-conditioned media (OACM), derived from OA obese (OA-ob:CM), OA-pre-obese (OA-Pob:CM), and mechanical stretch at either 0 %, 6 % or 10 % for 24 h. Differences in the mRNA levels of genes involved in extracellular matrix production, inflammation and secretory activity were measured.

RESULTS

Despite the significant BMI differences between the OA-ob and OA-Pob groups, OA-Pob has more patients with underlying dyslipidaemia, and low-grade synovitis with higher levels of secreted proteins, CXCL8, COL4A1, CCL4, SPARC and FGF2 in OA-Pob:CM. All primary SFb exhibited anti-proliferative activity with both OA-CM. Mechanical stretch stimulated lubricin production in scope:SFb, higher TGFβ1 and COL1A1 expressions in scope-CD:SFb. OA-Pob:CM stimulated greater detrimental effects than the OA-ob:CM, with higher pro-inflammatory cytokines, IL1β, IL6, COX2 and proteases such as aggrecanases, ADAMTS4 and ADAMTS5, and lower ECM matrix, COL1A1 expressions in all SFb. OA-ob:SFb were unresponsive but expressed higher pro-inflammatory cytokines under OA-Pob:CM treatment.

CONCLUSION

Both mechanical and inflammatory stressors regulate SFb molecular functions with heterogeneity in responses that are dependent on their pathological tissue of origins. While mechanical stretch promotes a favorable effect with enhanced lubricin production in scope:SFb and TGFβ1 and COL1A1 in scope-CD:SFb, the presence of excessively high OA-associated inflammatory mediators in OA-Pob:CM, predominantly SPARC, CXCL8 and FGF2 drive all SFb regardless of pathology, towards greater pro-inflammatory activities.

摘要

目的

通过比较 OA 患者队列中滑膜成纤维细胞（SFb）在机械负荷和炎症应激下的力学生物学反应，以更好地了解 SFb 的稳态功能。

方法

从 OA 肥胖（OA-ob）、OA 预肥胖（OA-Pob）、非 OA 关节镜（scope）和非 OA 关节镜伴软骨损伤（scope-CD）的膝关节滑膜中分离出原代 SFb，分别用 OA 肥胖患者来源的条件培养基（OA-ob:CM）、OA 预肥胖患者来源的条件培养基（OA-Pob:CM）和机械拉伸（0%、6%或 10%）处理 24 小时。测量参与细胞外基质产生、炎症和分泌活性的基因的 mRNA 水平差异。

结果

尽管 OA-ob 和 OA-Pob 组的 BMI 差异显著，但 OA-Pob 患者中更多的人存在潜在的血脂异常，且低级别滑膜炎伴更高水平的分泌蛋白，OA-Pob:CM 中 CXCL8、COL4A1、CCL4、SPARC 和 FGF2。所有原代 SFb 对 OA-CM 均表现出抗增殖活性。机械拉伸刺激 scope:SFb 分泌润滑素，scope-CD:SFb 中 TGFβ1 和 COL1A1 表达更高。OA-Pob:CM 刺激产生的有害作用大于 OA-ob:CM，OA-Pob:SFb 中促炎细胞因子 IL1β、IL6、COX2 和蛋白酶如 aggrecanases、ADAMTS4 和 ADAMTS5 水平更高，细胞外基质基质 COL1A1 表达水平更低。OA-ob:SFb 无反应，但在 OA-Pob:CM 处理下表达更高的促炎细胞因子。

结论

机械和炎症应激源均可调节 SFb 的分子功能，但反应存在异质性，这取决于其病理组织来源。机械拉伸促进了 scope:SFb 中润滑素产生的有利作用，以及 scope-CD:SFb 中 TGFβ1 和 COL1A1 的表达，但 OA-Pob:CM 中存在过高的 OA 相关炎症介质，主要是 SPARC、CXCL8 和 FGF2，使所有 SFb 产生更强的促炎活性，而不管其病理状态如何。