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Toward diagnostic relevance of the α V β 5 , α V β 3 , and α V β 6 integrins in OA: expression within human cartilage and spinal osteophytes
Bone Research ( IF 14.3 ) Pub Date : 2020-09-30 , DOI: 10.1038/s41413-020-00110-4
Edith Charlier 1 , Céline Deroyer 1 , Sophie Neuville 1 , Zelda Plener 1 , Olivier Malaise 1 , Federica Ciregia 1 , Philippe Gillet 2 , Gilles Reuter 3 , Mallory Salvé 4 , Nadia Withofs 4 , Roland Hustinx 4 , Dominique de Seny 1 , Michel G Malaise 1
Affiliation  

We previously reported 18FPRGD2 uptake by the coxofemoral lining, intervertebral discs and facet joint osteophytes in OA using PET/SCAN imaging. However, the molecular mechanism by which the PRGD2 tracer interacts with joint tissues and osteophytes in OA remains unclear. As PRGD2 ligands are expected to belong to the RGD-specific integrin family, the purpose of this study was (i) to determine which integrin complexes display the highest affinity for PRGD2-based ligands, (ii) to analyze integrin expression in relevant tissues, and (iii) to test integrin regulation in chondrocytes using OA-related stimuli to increase the levels of fibrosis and ossification markers. To this end, the affinity of PRGD2-based ligands for five heterodimeric integrins was measured by competition with 125I-echistatin. In situ analyses were performed in human normal vs. OA cartilage and spinal osteophytes. Osteophytes were characterized by (immuno-)histological staining. Integrin subunit expression was tested in chondrocytes undergoing dedifferentiation, osteogenic differentiation, and inflammatory stimulation. The integrins αVβ5, αVβ3, and αVβ6 presented the highest affinity for PRGD2-based ligands. In situ, the expression of these integrins was significantly increased in OA compared to normal cartilage. Within osteophytes, the mean integrin expression score was significantly higher in blood vessels, fibrous areas, and cells from the bone lining than in osteocytes and cartilaginous zones. In vitro, the levels of integrin subunits were significantly increased during chondrocyte dedifferentiation (except for β6), fibrosis, and osteogenic differentiation as well as under inflammatory stimuli. In conclusion, anatomical zones (such as OA cartilage, intervertebral discs, and facet joint osteophytes) previously reported to show PRGD2 ligand uptake in vivo expressed increased levels of αVβ5, αVβ3, and β6 integrins, whose subunits are modulated in vitro by OA-associated conditions that increase fibrosis, inflammation, and osteogenic differentiation. These results suggest that the increased levels of integrins in OA compared to normal tissues favor PRGD2 uptake and might explain the molecular mechanism of OA imaging using the PRGD2-based ligand PET/CT.



中文翻译:


OA 中 α V β 5 、α V β 3 和 α V β 6 整合素的诊断相关性:人软骨和脊柱骨赘中的表达



我们之前使用 PET/SCAN 成像报道了 OA 中髋股骨衬里、椎间盘和小关节骨赘对18 FPRGD 2 的摄取。然而,PRGD 2示踪剂与 OA 中关节组织和骨赘相互作用的分子机制仍不清楚。由于 PRGD 2配体预计属于 RGD 特异性整合素家族,本研究的目的是 (i) 确定哪些整合素复合物对基于 PRGD2 的配体表现出最高的亲和力,(ii) 分析相关组织中整合素的表达,以及 (iii) 使用 OA 相关刺激来测试软骨细胞中的整合素调节,以增加纤维化和骨化标记物的水平。为此,通过与125 I-echistatin竞争来测量基于PRGD 2的配体对五种异二聚体整联蛋白的亲和力。对人类正常软骨和脊柱骨赘进行原位分析。通过(免疫)组织学染色来表征骨赘。在经历去分化、成骨分化和炎症刺激的软骨细胞中测试了整合素亚基的表达。整合素α V β 5 、α V β 3和α V β 6对基于PRGD 2的配体表现出最高的亲和力。在原位,与正常软骨相比,这些整合素在 OA 中的表达显着增加。在骨赘中,血管、纤维区域和骨内层细胞的平均整合素表达评分显着高于骨细胞和软骨区域。 在体外,在软骨细胞去分化(β 6除外)、纤维化、成骨分化以及炎症刺激下,整合素亚基的水平显着增加。总之,先前报道的解剖区域(例如 OA 软骨、椎间盘和小关节骨赘)显示体内 PRGD 2配体摄取表达增加的 α V β 5 、α V β 3和 β 6整合素水平,其亚基在体外受到 OA 相关条件的调节,增加纤维化、炎症和成骨分化。这些结果表明,与正常组织相比,OA 中整合素水平的增加有利于 PRGD2 的摄取,并可能解释使用基于 PRGD 2的配体 PET/CT 进行 OA 成像的分子机制。

更新日期:2020-09-30
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