Peculiarities in Ankle Cartilage

Abstract

Posttraumatic osteoarthritis (PTOA) is the most common form of osteoarthritis (OA) of the ankle joint. PTOA occurs as a result of several factors, including the poor regenerative capacity of hyaline articular cartilage as well as increased contact stresses following trauma. The purpose of this article is to review the epidemiology, pathogenesis, and potential targets for treatment of PTOA in the ankle joint. Previous reviews primarily addressed clinical approaches to ankle PTOA, while the focus of the current article will be specifically on the newly acquired knowledge of the cellular mechanisms that drive PTOA in the ankle joint and means for potential targeted therapeutics that might halt the progression of cartilage degeneration and/or improve the outcome of surgical interventions. Three experimental treatment strategies are discussed in this review: (1) increasing the anabolic potential of chondrocytes through treatment with growth factors such as bone morphogenetic protein-7; (2) limiting chondrocyte cell death either through the protection of cell membrane with poloxamer 188 or inhibiting activity of intracellular proteases, caspases, which are responsible for cell death by apoptosis; and (3) inhibiting catabolic/inflammatory responses of chondrocytes by treating them with anti-inflammatory agents such as tumor necrosis factor-α antagonists. Future studies should focus on identifying the appropriate timing for treatment and an appropriate combination of anti-inflammatory, chondro- and matrix-protective biologics to limit the progression of trauma-induced cartilage degeneration and prevent the development of PTOA in the ankle joint.

Keywords: ankle; anti-inflammatory; cartilage; chondroprotection; posttraumatic osteoarthritis.

Figure 1.

Changes in morphological appearance of the ankle and knee cartilage from human organ donors with no documented history of joint disease with age and degeneration as defined by the Collins morphology scale^,.

Figure 2.

Cell viability. Total refers to all layers of cartilage explant (superficial, middle, deep). All agents were added to parallel cultures immediately after impaction on day 0 and were kept for 48 hours, after which they were replaced with fresh media only. Measurements were made on day 0 immediately following impaction, and then on days 2, 7, and 14. IC = impacted control; OP-1 = osteogenic protein-1 added at 100 ng/mL concentration; TNF = tumor necrosis factor-α (TNF-α) antagonist, 100 ng/mL; NAC = N-acetyl-l-cysteine, 2.5 mM; IL-RA = IL-1 receptor antagonist used at 20 ng/mL and 100 ng/mL; Pan-caspase inhibitor Z = Z-VAD-FMK pan caspase inhibitor, 100 µM; Pan-caspase inhibitor Q = Q-VD-OPh pan caspase inhibitor, 100 µM. Cell viability was assessed with Live/Dead Cell assay.

Figure 3.

Effect of combined treatment on chondrocyte viability and proteoglycan synthesis in the model of ankle acute injury as described in Pascual-Garrido et al. (A) Schematic representation of combo groups. (B) Cell viability as measured by Live/Dead Cell assay. UIC = un-impacted control; IC = impacted control. (C) Representative images of cartilage sections stained with calcein AM (green fluorescence, live cells) and ethidium bromide homodimer-1 (red fluorescence, dead cells) (Molecular Probes, Eugene, OR). (D) Proteoglycan synthesis was measured as described: the cells were labeled with 5 µCi/mL S-sulfate (Perkin Elmer, Boston, MA) for 4 hours. The amount of S-labeled PGs was analyzed by the alcian blue (Bio-Rad, Hercules, CA) precipitation method; the values were normalized to the wet weight of each cartilage explant. All measurements were done in triplicate for each donor sample.