Cytokine networking of chondrocyte dedifferentiation in vitro and its implications for cell-based cartilage therapy

Abstract

Autologous chondrocyte implantation (ACI) is a golden treatment for large defects of the knee joint without osteoarthritis or other complications. Despite notable progresses, generation of a stable chondrocyte phenotype using progenitor cells remains a main obstacle for chondrocyte-based cartilage treatment. Monolayer chondrocyte expansion in vitro is accompanied by chondrocyte dedifferentiation, which produces a non-specific mechanically inferior extracellular matrix (ECM) unsuitable for ACI. In-depth understanding of the molecular events during chondrocyte dedifferentiation is required to maintain the capacity of in vitro expanded chondrocytes to produce hyaline cartilage-specific ECM. This review discusses key cytokines and signaling pathways involved in chondrocyte dedifferentiation from the standpoint of catabolism and anabolism. Some potential therapeutic strategies are also presented to counteract chondrocyte dedifferentiation for cell-based cartilage therapy.

Keywords: Chondrocyte dedifferentiation; autologous chondrocyte implantation; cartilage repair; cytokines; in vitro; signaling pathways.

Figure 1

Autologous chondrocyte implantation. A. Cartilage biopsy was harvested from a non-weight bearing area of the knee joint under an arthoscope. B. Around 100 mg cartilage was harvested and enzymatically digested. Chondrocytes were propagated in a GMP lab. C. During the second operation, a collagen membrane was trimmed according to the defect size. D. The periosteum was sutured. E. Chondrocytes were injected into the space between the membrane and the defect. F. After chondrocyte injection, the membrane was sealed with fibrin glue to prevent leaking.

Figure 2

Chondrocyte dedifferentiation during in vitro expansion. Primary human chondrocyte morphology under invert microscope (×100). With passaging, round and polygonal chondrocytes were shifted to fibroblast-like cells. A (P0), B (P1), C (P2), D (P4).

Figure 3

Schematic illustration of molecular events in chondrocyte dedifferentiation. Multiple signaling pathways are evoked during chondrocyte undergoing stimulants, including catabolic factors (IL-1β, IL-6, FGF-18) and anabolic factors (IGF-I, BMP-2, TGF-β). MAPK, PI3K/AKT, PKC, WNT, and Notch proteins are involved in regulating the ratio of COL-2 and COL-1, a key indicator of chondrocyte dedifferentiation. The red dash indicates inhibition and the black arrow indicates promotion.