Phenotypic Variations in Chondrocyte Subpopulations and Their Response to In Vitro Culture and External Stimuli

Abstract

Articular cartilage defects have limited capacity to self-repair, and cost society up to 60 billion dollars annually in both medical treatments and loss of working days. Recent developments in cartilage tissue engineering have resulted in many new products coming to market or entering clinical trials. However, there is a distinct lack of treatments which aim to recreate the complex zonal organization of articular cartilage. Cartilage tissue withstands repetitive strains throughout an individual's lifetime and provides frictionless movement between joints. The structure and composition of its intricately organized extracellular matrix varies with tissue depth to provide optimal resistance to loading, ensure ease of movement, and integrate with the subchondral bone. Each tissue zone is specially designed to resist the load it experiences, and maximize the tissue properties needed for its location. It is unlikely that a homogenous solution to tissue repair will be able to optimally restore the function of such a heterogeneous tissue. For zonal engineering of articular cartilage to become practical, maintenance of phenotypically stable zonal cell populations must be achieved. The chondrocyte phenotype varies considerably by zone, and it is the activity of these cells that help achieve the structural organization of the tissue. This review provides an examination of literature which has studied variations in cellular phenotype between cartilage zones. By doing so, we have identified critical differences between cell populations and highlighted areas of research which show potential in the field. Current research has made the morphological and metabolic variations between these cell populations clear, but an ideal way of maintaining these differences in vitro culture is yet to be established. Combinations of delivered growth factors, mechanical loading, and layered three-dimensional culture systems all show potential for achieving this goal. Furthermore, differentiation of progenitor cell populations into chondrocyte subpopulations may also hold promise for achieving large numbers of zonal chondrocytes. Success of the field lies in establishing methods of retaining phenotypically stable cell populations for in vitro culture.

Protocatechuic acid benefits proliferation and phenotypic maintenance of rabbit articular chondrocytes: An in vitro study

“…Dedifferentiation of articular chondrocytes tends to appear as the culture time progresses in tissue engineering or in the development of OA (11,33). Simultaneously, non-cartilage-specific ECM is produced, which is characteristic of a poor biomechanical response.…”

“…Tissue engineering, where cells can be encapsulated in a carrier matrix, is a promising alternative resolution although arthroplasty is time consuming and microfracture suitable for minor lesions (9). Sustained phenotypic maintenance of chondrocytes during expansion in vitro, and the synthesis of mature ECM combined with anti-inflammation following transplantation in vivo, are necessary for the successful treatment of OA with tissue engineering (10,11), which remains a serious challenge and requires further research.…”

Chemical changes demonstrated in cartilage by synchrotron infrared microspectroscopy in an antibody-induced murine model of rheumatoid arthritis

“…10 The ECM comprises a network of collagen fibers, mainly CII, in which are enmeshed a variety of sulphated glycoproteins, particularly aggrecan and the unsulphated glyosaminoglycan hyaluronan. 10,11 Collagen, primarily CII, comprises approximately 10-20% of the wet weight of the cartilage 10 and provides the tensile strength of the cartilage matrix.…”

“…10 The ECM comprises a network of collagen fibers, mainly CII, in which are enmeshed a variety of sulphated glycoproteins, particularly aggrecan and the unsulphated glyosaminoglycan hyaluronan. 10,11 Collagen, primarily CII, comprises approximately 10-20% of the wet weight of the cartilage 10 and provides the tensile strength of the cartilage matrix. 10,12 These interactions are essential for the structural stability of cartilage, and we postulate that arthritogenic mAbs cause cartilage damage by binding specifically to critical structural regions on collagen fibrils that are sites of interaction between CII and matrix components or chondrocytes.…”

Engineering Superficial Zone Chondrocytes from Mesenchymal Stem Cells

“…The superficial zone is distinct from the middle and deep zones both in matrix composition and cellular function. 1 Superficial zone chondrocytes are the only zonal population to secrete elevated levels of proteoglycan-4 (PRG4), 2,3 a protein that can complex with hyaluronic acid, 4 and is a critical component of joint lubrication. 5 PRG4 is homologous to the lubricating proteins lubricin 6 and superficial zone protein, 7 which are all encoded by the PRG4 gene.…”