Cartilage Cell Clusters

Cell organization in clusters represents an interesting and, as yet, not well-characterized phenomenon in normal articular cartilage, in tissue responses to chemical or mechanical injury, and prominently in cartilage affected by diseases such as OA. Cluster formation also occurs readily in culture models, suggesting an intrinsic tendency and capacity of certain cartilage cells to assume this cellular organization. It can be proposed that repair of cartilage lesions that include both ECM damage and cell death would require replication of some of the cells adjacent to the damaged area, followed by migration, differentiation, and new matrix formation (140). It appears that cluster formation represents the first phase of this response. Clusters are seen with a remarkable uniformity in cartilage exposed to a broad range of injuries that are always associated with some degree of cell death. Whether any surviving cell or only certain subsets of cells are able to proliferate and form clusters is unknown. An interesting hypothesis is that proliferation is a function of immature or progenitor cells. The triggers for cell proliferation may include loss of cell-cell interactions due to cell death. Liberation of growth factors such as FGF-2 from damaged tissue appears to be an important mechanism for the generation of mitogenic stimuli, at least during the initial stages of cluster formation (Figure 6). The rate and size of cluster formation depend on the type of injury and maturity of cartilage. Cells within clusters have certain features suggesting that they can migrate, but whether cells do indeed migrate from the clusters to acellular areas of cartilage is an unresolved question that is important in order to understand intrinsic cartilage repair and cartilage engineering approaches. Movements of single cells or collective movements of interconnected groups or clusters of cells have recently been characterized as important mechanisms in tissue and organ development (142). Cell-cell adhesions, cell-matrix interactions, contractility, and the ability of cells to form protrusions and migrate as described for the cluster cells contribute to active motility. Tissue engineering of chondral and osteochondral grafts is being actively pursued as a potential method of surgically repairing cartilage lesions. Cluster formation occurs in 3-dimensional cultures of chondrocytes and needs to be carefully evaluated in engineered constructs using scaffolds with stem cells. Spontaneous chondrocyte cluster formation has also been noted in osteochondral allografts in several animal models (66). These clusters did not appear to express the abnormal markers seen in OA clusters. However, it must be noted that these studies were conducted in tissue or cells from young adult animals and in joints that did not have an inflammatory response. Collectively, the findings raise a concern regarding tissue engineering during the preimplantation cell proliferation and matrix generation phases, as well as the postoperative phase after implantation in the chondral lesion. Clusters that form in arthritic articular cartilage contain cells that express a large number of pathogenic mediators and thus appear at the site of much of the increased biosynthetic activity that characterizes OA cartilage. The activation patterns are those of a disordered or mixed differentiation phenotype. This may be due to the influence of inflammation mediators produced in the clusters or by other inflamed joint tissues. The activation of cluster cells and their products appear to contribute to the manifestations of cartilage diseases such as ECM degradation and calcification, and joint inflammation. The cluster cells illustrate the ability of a subpopulation of cartilage cells to undergo activation and proliferation, even in older individuals. Correcting the abnormal differentiation and harnessing the reparative potential of these cells pharmacologically may offer new approaches to cartilage repair and OA therapy. © 2010, American College of Rheumatology.