Stone A V, Loeser R F, Vanderman K S, Long D L, Clark S C, Ferguson C M
Department of Orthopaedic Surgery, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Osteoarthritis Cartilage. 2014 Feb;22(2):264-74. doi: 10.1016/j.joca.2013.11.002. Epub 2013 Dec 4.
Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development.
Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties (TKAs) was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide.
Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor (CTGF) gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production.
Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.
半月板损伤会增加骨关节炎的风险；然而，其生物学机制仍不清楚。我们推测，半月板的促炎刺激会增加基质降解酶、细胞因子和趋化因子的产生，这些物质会导致关节组织破坏，并可能促使骨关节炎的发展。
培养来自健康组织供体和全膝关节置换术（TKA）的半月板和软骨组织。用促炎因子[白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）或纤连蛋白片段（FnF）]刺激原代细胞培养物，并通过实时聚合酶链反应、蛋白质阵列和免疫印迹分析细胞反应。为了确定基质金属蛋白酶（MMP）产生是否需要核因子κB（NF-κB），用有无NF-κB抑制剂己烷雌酚的炎性因子处理半月板培养物。
正常和骨关节炎半月板细胞在受到刺激后其MMP分泌增加，但每种刺激都出现了独特的特定模式，对FnF反应时表达的MMP数量最多。半月板胶原蛋白和结缔组织生长因子（CTGF）基因表达降低。细胞因子（IL-1α、IL-1β、IL-6）、趋化因子（IL-8、CXCL1、CXCL2、集落刺激因子1）以及NF-κB和肿瘤坏死因子（TNF）家族成分的表达显著增加。刺激也增加了细胞因子和趋化因子的蛋白质产生。当原代细胞培养物在促炎刺激的同时用己烷雌酚处理时，p65激活减少，MMP-1和MMP-3产生也减少。
半月板细胞的促炎刺激增加了基质金属蛋白酶的产生和分解代谢基因的表达。半月板在关节损伤后骨关节炎的发展中可能通过增加细胞因子、趋化因子和基质降解酶的产生而发挥积极的生物学作用。
