Cell-based articular cartilage repair: the link between development and regeneration

Abstract

Clinical efforts to repair damaged articular cartilage (AC) currently face major obstacles due to limited intrinsic repair capacity of the tissue and unsuccessful biological interventions. This highlights a need for better therapeutic strategies. This review summarizes the recent advances in the field of cell-based AC repair. In both animals and humans, AC defects that penetrate into the subchondral bone marrow are mainly filled with fibrocartilaginous tissue through the differentiation of bone marrow mesenchymal stem cells (MSCs), followed by degeneration of repaired cartilage and osteoarthritis (OA). Cell therapy and tissue engineering techniques using culture-expanded chondrocytes, bone marrow MSCs, or pluripotent stem cells with chondroinductive growth factors may generate cartilaginous tissue in AC defects but do not form hyaline cartilage-based articular surface because repair cells often lose chondrogenic activity or result in chondrocyte hypertrophy. The new evidence that AC and synovium develop from the same pool of precursors with similar gene profiles and that synovium-derived chondrocytes have stable chondrogenic activity has promoted use of synovium as a new cell source for AC repair. The recent finding that NFAT1 and NFAT2 transcription factors (TFs) inhibit chondrocyte hypertrophy and maintain metabolic balance in AC is a significant advance in the field of AC repair. The use of synovial MSCs and discovery of upstream transcriptional regulators that help maintain the AC phenotype have opened new avenues to improve the outcome of AC regeneration.

Keywords: Articular cartilage repair; Cartilage tissue-engineering; NFAT; Post-traumatic osteoarthritis; Stem cell; Synovium.

Figure 1

A diagram showing proposed mechanisms for the development of major joint tissues. Upper panels: The interzone is distinguishable into a central intermediate zone and two outer layers contiguous to the epiphyseal ends. Interzone cells from the intermediate layer contribute to the formation of AC, synovial lining, and intra-articular ligaments. Interzone cells from the outer layers differentiate into chondrocytes and become incorporated into the epiphysis, which undergoes endochondral ossification. Dotted arrows indicate that further elucidation is required. Lower panels: The development of the secondary ossification center (SOC) begins with the formation of cartilage canal containing blood vessels, followed by chondrocyte hypertrophy and endochondral ossification in the center of the epiphyseal cartilage.

Figure 2

Photomicrographs of a representative mouse patellofemoral joint with a osteochondral defect created in the patellar groove of the distal femur (left) and a mouse patellofemoral joint received sham surgery (arthrotomy only, right) at 6 weeks after surgery. Cartilage is stained in red. Six mice from each group were evaluated at this time point. Top left: A patellofemoral joint with an osteochondral defect (arrow) and chondrocyte differentiation in the synovium that is attached to the joint margins (arrowheads). Middle left: A micrograph enlarged from the yellow box in the top left panel shows the differentiation of synovial cells into chondrocytes (arrowhead) forming new cartilage in the synovial plica. Bottom left: A micrograph with higher magnification shows that the osteochondral defect (arrow) is filled with new cartilage cells (red) in the lower portion of the defect and fibrous tissue in the upper defect. Top right: A patellofemoral joint that received sham surgery shows a normal synovial plica (open arrow in the black box). Middle right: A normal synovial plica (open arrow) enlarged from the black box in the top right panel shows normal synovial lining and subsynovial fibrous tissue. Bottom right: A patellar groove of the distal femur without an osteochondral defect shows essentially normal articular cartilage and subchondral bone. Safranin-O and fast green staining, counterstained with haematoxylin.

Figure 3

An illustration demonstrates that catabolic and anabolic factors that may be responsible for the development of OA and the possible role of NFAT1 in preventing the initiation or attenuating the progression of OA.