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首页> 外文期刊>Osteoarthritis and cartilage >Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis.
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Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis.

机译：骨关节炎患者细胞中胶原酶3内吞受体系统的损伤。

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OBJECTIVE: Collagenase-3, a matrix metalloproteinase (MMP-13) that can degrade collagen II and aggrecan, is produced by osteoarthritic (OA) chondrocytes and may contribute to matrix destruction in this disease. Our laboratory has previously identified a specific endocytotic receptor for collagenase-3 on osteoblastic and fibroblastic cells, which couples with the low-density lipoprotein receptor-related protein (LRP1) to mediate the internalization and degradation of this enzyme. We hypothesized that the activity of this receptor system is reduced in OA chondrocytes which may lead to increased local extracellular levels of collagenase-3 and increased destruction of the cartilage matrix at pericellular sites. METHODS: Human chondrocytes and synoviocytes were obtained from OA knees at the time of joint replacement surgery and from non-arthritic control specimens following autopsy or surgery. Enzyme-linked immunosorbant assay (ELISA) was used to measure collagenase-3 secreted from primary cultures. Iodinated collagenase-3 was used to analyze the cell-surface binding, internalization and intracellular degradation of collagenase-3. Reverse-transcriptase polymerase chain reaction was used to confirm chondrocyte phenotype and the expression of collagenase-3 and LRP1 mRNAs. RESULTS: OA chondrocytes and synoviocytes demonstrated significantly reduced (75-77%) binding of recombinant 125I collagenase-3. Internalization and degradation of the ligand was also significantly reduced (64-72%) in OA cells. Collagenase-3 removal was inhibited by the LRP1 receptor-associated protein (RAP). CONCLUSION: These results suggest a mechanism whereby impaired receptor-mediated removal of collagenase-3 in OA chondrocytes may lead to enhanced local degradation of the cartilage matrix. This work also implicates an LRP family member in endocytotic receptor-mediated collagenase-3 processing and suggests a novel therapeutic target for OA.
机译：目的：胶原酶-3（一种基质金属蛋白酶（MMP-13），可以降解II型胶原和蛋白聚糖），是由骨关节炎（OA）软骨细胞产生的，可能导致该疾病的基质破坏。我们的实验室以前已经鉴定了成骨细胞和成纤维细胞上胶原酶3的特异性内吞受体，该受体与低密度脂蛋白受体相关蛋白（LRP1）偶联以介导该酶的内在化和降解。我们假设该受体系统的活性在OA软骨细胞中降低，这可能导致局部胶原蛋白-3的细胞外水平增加和在细胞周围位点的软骨基质破坏增加。方法：人软骨细胞和滑膜细胞取自关节置换手术时的OA膝关节，以及尸体解剖或手术后的非关节炎对照标本。酶联免疫吸附测定（ELISA）用于测量从原代培养物中分泌的胶原酶3。碘化胶原酶3用于分析胶原酶-3的细胞表面结合，内在化和细胞内降解。用逆转录酶聚合酶链反应确认软骨细胞表型以及胶原酶3和LRP1 mRNA的表达。结果：OA软骨细胞和滑膜细胞显示重组125 I胶原酶3的结合显着降低（75-77％）。在OA细胞中，配体的内化和降解也显着降低（64-72％）。 LRP1受体相关蛋白（RAP）抑制了胶原酶3的去除。结论：这些结果提示了一种机制，其中OA软骨细胞中受体介导的胶原酶-3去除受损可能导致软骨基质的局部降解增强。这项工作还暗示内吞受体介导的胶原酶3加工中的LRP家族成员，并建议新的OA治疗靶点。

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