Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1
Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1
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DOI：
10.1369/jhc.2009.953893
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发表时间：
2009-10-01
影响因子：
3.2
通讯作者：
Horton, Walter E., Jr.
中科院分区：
文献类型：
--
作者：
Nugent, Ashleigh E.;Speicher, Danielle M.;Horton, Walter E., Jr.
为了验证内质网（ER）功能紊乱参与骨关节炎（OA）发病机制的假设，从继发于骨肉瘤或软骨肉瘤切除术的非OA患者中分离关节软骨。从接受全膝关节置换术的患者中分离出关节内最小和晚期骨关节炎软骨样本，并对疾病严重程度进行评分。通过免疫荧光检测葡萄糖调节蛋白-78（grp 78）和bcl-2相关的产气基因-1（bag-1）作为非稳态ER功能的标志物。此外，测定VI型胶原及其整合素受体NG 2的表达以检查软骨基质的健康和周转。grp 78在晚期OA中表达上调，在轻度OA中表达可变。非OA软骨始终为grp 78阴性。与正常软骨相比，OA中的下游调节因子bag-1也上调。VI型胶原在非OA软骨中主要与细胞相关，在OA软骨中观察到更广泛的分布，沿着细胞内染色强度增加。与患者匹配的最小受累软骨样本相比，晚期OA中VI型胶原整合膜蛋白聚糖受体NG 2下调。这些结果表明，软骨细胞在OA过程中表现出ER应激，与一个大的分泌分子VI型胶原的上调有关。（J Histochem Cytochem 57：923-931，2009）
To test the hypothesis that a perturbation of endoplasmic reticulum (ER) function is involved in the pathogenesis of osteoarthritis (OA), articular cartilage was isolated from non-OA patients secondary to resection of osteo-or chondrosarcomas. Intra-joint samples of minimal and advanced osteoarthritic cartilage were isolated from patients undergoing total knee arthroplasty and scored for disease severity. Glucose-regulated protein-78 (grp78) and bcl-2-associated athanogene-1 (bag-1) were detected via immunofluorescence as markers of non-homeostatic ER function. Additionally, the expression of type VI collagen and its integrin receptor, NG2, was determined to examine cartilage matrix health and turnover. There was an upregulation of grp78 in advanced OA, and variable expression in minimal OA. Non-OA cartilage was consistently grp78 negative. The downstream regulator bag-1 was also upregulated in OA compared with normal cartilage. Collagen VI was mainly cell-associated in non-OA cartilage, with a more widespread distribution observed in OA cartilage along with increased intracellular staining intensity. The collagen VI integral membrane proteoglycan receptor NG2 was downregulated in advanced OA compared with its patient-matched minimally involved cartilage sample. These results suggest that chondrocytes exhibit ER stress during OA, in association with upregulation of a large secreted molecule, type VI collagen. (J Histochem Cytochem 57:923-931, 2009)