Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes

Abstract

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.

Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice

“…A group of mechanosensing and mechanotransducing molecules may be regulated over PT-OA development and tune cellular mechano-sensitivity under abnormal joint mechanics and inflammation post-ACL-I. For instance, dysregulated integrin α V β 3 and their associated ligands may play essential roles in disrupting chondrocyte-ECM interactions over OA progression [ [47] , [48] , [49] ], as well as Piezo1 may be augmented via IL-1-mediated inflammatory patho-mechanisms [ 50 ]. This study has explored female mice but not male mice, also mechanically-induced chondrocyte death are quantified using living cells in the native tissues, ex vivo and in situ, post-ACL-injuries, but not compared with histological assays, such as TUNEL/Necrosis assays.…”

Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice

“…A group of mechanosensing and mechanotransducing molecules may be regulated over PT-OA development and tune cellular mechano-sensitivity under abnormal joint mechanics and inflammation post-ACL-I. For instance, dysregulated integrin αVβ3 and their associated ligands may play essential roles in disrupting chondrocyte-ECM interactions over OA progression [77][78][79] , as well as Piezo1 may be augmented via IL-1-mediated inflammatory patho-mechanisms 80,81 . Future research will investigate the chondrocyte mechano-vulnerability based on mechanosensors and mechanotransducers and their local ECM properties over PT-OA development.…”

Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381–397 a.a.) competing for TGF-β1 activation

“…Integrins differ in tissue distribution and ligand identification. Recently, it has been reported that α V β 5 , α V β 3 , and α V β 6 interact with PRGD 2 , and their expression levels are increased in osteoarthritic cartilage and osteophytes 11 . Integrin α V β 6 interacts with molecules that contain the Arg-Gly-Asp (RGD) motif.…”