Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty.
Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty.
复制标题
DOI：
10.1186/1755-1536-3-17
复制
发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Steinbeck MJ
中科院分区：
文献类型：
--
作者：
Freeman TA;Parvizi J;Dela Valle CJ;Steinbeck MJ
特发性关节纤维化发生在3-4%接受全膝关节置换术（TKA）的患者中。然而，很少有人知道的细胞或分子的变化参与发病或进展的这种情况。为了对组织形态学变化进行分类并评估潜在的影响因素，分析了关节纤维化患者膝关节周围组织的成纤维细胞和肥大细胞增殖、异位骨化、细胞凋亡、缺氧和氧化应激。关节纤维化组织由致密的成纤维细胞区域组成，沿外缘沿着有有限的血管分布。在纤维化区域内，观察到糜蛋白酶/成纤维细胞生长因子（FGF）表达肥大细胞数量增加。此外，该区域含有纤维软骨和相关的异位骨化，这与活动度降低（僵硬）定量相关。纤维化，纤维软骨和骨化的地区包含几个终端dUTP缺口末端标记（TUNEL）阳性或凋亡细胞，尽管乳酸脱氢酶（LDH）5，缺氧的标志物，和硝基酪氨酸，蛋白质亚硝基化的标志物阳性免疫染色。LDH 5和硝基酪氨酸被发现在相同的组织区域，表明组织内的缺氧区域与活性氧和氮的产生增加。总之，我们认为缺氧相关的氧化应激启动肥大细胞增殖和FGF分泌，刺激成纤维细胞增殖和组织纤维化。在这种缺氧环境中的成纤维细胞经历化生转化为纤维软骨，然后异位骨化，导致关节僵硬增加。因此，缺氧和相关的氧化应激是TKA后特发性关节纤维化的纤维化和化生进展的潜在治疗靶点。
Idiopathic arthrofibrosis occurs in 3-4% of patients who undergo total knee arthroplasty (TKA). However, little is known about the cellular or molecular changes involved in the onset or progression of this condition. To classify the histomorphologic changes and evaluate potential contributing factors, periarticular tissues from the knees of patients with arthrofibrosis were analyzed for fibroblast and mast cell proliferation, heterotopic ossification, cellular apoptosis, hypoxia and oxidative stress. The arthrofibrotic tissue was composed of dense fibroblastic regions, with limited vascularity along the outer edges. Within the fibrotic regions, elevated numbers of chymase/fibroblast growth factor (FGF)-expressing mast cells were observed. In addition, this region contained fibrocartilage and associated heterotopic ossification, which quantitatively correlated with decreased range of motion (stiffness). Fibrotic, fibrocartilage and ossified regions contained few terminal dUTP nick end labeling (TUNEL)-positive or apoptotic cells, despite positive immunostaining for lactate dehydrogenase (LDH)5, a marker of hypoxia, and nitrotyrosine, a marker for protein nitrosylation. LDH5 and nitrotyrosine were found in the same tissue areas, indicating that hypoxic areas within the tissue were associated with increased production of reactive oxygen and nitrogen species. Taken together, we suggest that hypoxia-associated oxidative stress initiates mast cell proliferation and FGF secretion, spurring fibroblast proliferation and tissue fibrosis. Fibroblasts within this hypoxic environment undergo metaplastic transformation to fibrocartilage, followed by heterotopic ossification, resulting in increased joint stiffness. Thus, hypoxia and associated oxidative stress are potential therapeutic targets for fibrosis and metaplastic progression of idiopathic arthrofibrosis after TKA.