Using two-dimensional top-down view microscopy, researchers have recently described chondrocytes as being spatially arranged in distinct patterns such as strings, double strings, and small and large clusters. Because of the seeming association of these changes with tissue degeneration, they have been proposed as an image-based biomarker for early osteoarthritis (OA) staging. The aim of our study was to investigate the spatial arrangement of chondrocytes in human articular cartilage in a 3D fashion and to evaluate the 3D changes of these patterns in the context of local tissue destruction. Decalcified femoral condyle resections from the load-bearing area were analysed in 3D for their spatial chondrocyte organisation by means of fluorescence microscopy and synchrotron-radiation micro-computed tomography (SR-µCT). In intact cartilage chondrocyte strings can be found in the superficial, transitional and deep zones. The proposed pattern changes accompanying tissue destruction could be located not just along the surface but also through all layers of cartilage. Each spatial pattern was characterised by a different cellular density (the only exception being between single and double strings with p = 0.062), with cellular density significantly increasing alongside the increase in local tissue degeneration as defined by the chondrocyte patterns. We can thus corroborate that the proposed cellular spatial changes are a three-dimensional function of local tissue degeneration, underlining their relevance as an image-based biomarker for the early diagnosis and description of OA.Clinical trial registration number: Project number of the ethics committee of the University of Tübingen:171/2014BO2.
During osteoarthritis, chondrocytes change their spatial arrangement from single to double strings, then to small and big clusters. This change in pattern has recently been established as an image‐based biomarker for osteoarthritis. The pericellular matrix (PCM) appears to degrade together alongside cellular reorganization. The aim of this study was to characterize this PCM‐degradation based on different cellular patterns. We additionally wanted to identify the earliest time point of PCM‐breakdown in this physiopathological model. To this end, cartilage samples were selected according to their predominant cellular pattern. Qualitative analysis of PCM degradation was performed immunohistochemically by analysing five main PCM components: collagen type VI, perlecan, collagen type III, biglycan, and fibrillin‐1 (n = 6 patients). Their protein content was quantified by enzyme‐linked immunosorbent assay (127 patients). Accompanying spatial cellular rearrangement, the PCM is progressively destroyed, with a pericellular signal loss in fluorescence microscopy for collagen type VI, perlecan, and biglycan. This loss in protein signal is accompanied by a reduction in total protein content from single strings to big clusters (P < .001 for collagen type VI, P = .003 for perlecan, and P < .001 for biglycan). As a result of an increase in the number of cells from single strings to big clusters, the amount of protein available per cell also decreases for collagen type III and fibrillin‐1, where total protein levels remain constant. Biochemical changes of the PCM and cellular rearrangement are thus highly interconnected hallmarks of osteoarthritis. Interestingly, the earliest point in time for a relevant PCM impairment appears to be at the transition to small clusters.
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