Reducing the acute influx of inflammatory leukocytes into cartilage that has been damaged by trauma and ischemic injury might be one way to limit the extent of damage to articular surfaces after joint injuries. Cartilage has little ability to repair itself, and the incoming wave of leukocytes actually extends the area of injury and chondrocyte death far beyond the site of cartilage damage, investigators report in the May issue of Arthritis & Rheumatism.¹

While leukocytes may initially worsen tissue damage, they ultimately promote tissue repair. "Considering the limited regenerative potential of cartilage, tissue injury caused by leukocytes might outweigh any reparative phase they might direct," the researchers from the Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center write.

Using fresh cadaveric canine femoral condyles subjected to impact injury, the investigators found that chondrocytes even 10 mm from the impact site died within 7 days after injury. The cell death appears to be due to generation of nitric oxide (NO), as the death can be prevented by inhibiting NO generation.

Cells within the 10-mm "danger zone" are also directly killed by mononuclear leukocytes. Chondrocytes in this area expressed intercellular adhesion molecule 1 (ICAM-1, CD54), to which leukocytes bind. According to senior author Holly Hyde Birdsall, MD, PhD, of the Veterans Affairs Medical Center in Houston, Texas, the extensive chondrocyte death after cartilage injury could be blocked by using desferoxamine or anti-CD18 antibodies to prevent leukocytes from attaching to ICAM-1.

The ICAM-1 gene in endothelial cells responds to shear stress, and the investigators suspect that similar shear stress response elements within chondrocytes are triggered by certain types of injury.

Dr. Birdsall and lead study author David Green, MD, are also part of a team that has been investigating the role of leukocytes in extending the zone of injury in animal models of myocardial infarction (MI). Attempts to reduce the extent of MI-related heart damage with an anti-CD18 antibody have not been successful in humans.

"We are well aware of the difficulties in implementing blocking therapies," Dr. Birdsall said. "I do not think anti-CD18 will be any more successful in cartilage injury than it is in other injuries. The trick in all of these tissue injuries will be to figure out exactly which cells one wants to prevent from entering into the area and for how long. Clearly a global inhibition of leukocyte migration is hard to implement, and prevents the influx of leukocytes into areas where they are needed quickly, such as infections," Dr. Birdall explained, adding, "It is also clear that certain leukocytes are needed to orchestrate the healing, both by clearing away dead cells and by bringing in replacement cells or scar tissue. Therefore, you don't want to block leukocyte influx for too long."

Reference

1. Green DM, Noble PC, Ahuero JS, Birdsall HH. Cellular events leading to chondrocyte death after cartilage impact injury. Arthritis Rheum. 2006;54:1509-1517.