Enzyme may lead to arthritis treatment

Scientists have found a new role for a previously identified enzyme that may make it a target for anti-inflammatory treatments.

School of Medicine research has revealed that an enzyme called cathepsin G regulates the ability of immune cells known as neutrophils to secrete chemicals that attract other immune cells and start the local inflammatory process.

Over time, the excessive accumulation of immune cells can lead to tissue and cartilage damage in joints, causing pain and limiting mobility.

“Cathepsin G affects a very early step in this kind of immune response, so inhibiting it has attractive potential for developers of therapeutics,” said senior author Christine T.N. Pham, M.D., assistant professor of medicine and of pathology and immunology.

The study appeared in the June issue of Immunity.

Cathepsin G, which is made by the neutrophils it regulates, also is an attractive target because it belongs to a class of enzymes known as proteases.

One principal type of HIV treatment inhibits proteases, so scientists who try to block cathepsin G’s role in inflammation already have extensive research to reference.

Pham’s team used mouse models of arthritis to study the contributions of proteases and other factors to inflammation and arthritis. One such model involved injecting mice with collagen from calf joints.

“The mice make antibodies to that protein because it’s somewhat foreign, but the antibodies have enough cross-reactivity that they will bind to the mouse’s own cartilage and collagen and initiate an inflammation,” Pham said.

“This leads to a condition similar to rheumatoid arthritis in the mice.”

Three years ago, Pham’s team published research showing mice deficient in cathepsin G and other closely related proteases failed to develop arthritis after the injections.

This led the team to look for the mechanisms by which these proteases regulate inflammation.

Observations made by Pham’s team and other groups had linked the earliest stages of inflammation in animal models to neutrophils, which are a kind of immune system firestarter.

They arrive first at sites of injury, infection or irritation and secrete chemicals that bring in secondary waves of other immune attack cells.

“The contributions of the neutrophil weren’t always appreciated by scientists,” Pham said.

“When patients come to doctors with arthritis symptoms, the inflammation typically is so well-established that neutrophils are no longer the predominant cell type.”

Animal models of inflammation let scientists watch all stages of the inflammatory process and allow them to see how important neutrophils are to the early stages of that process.

In the new study, Pham and her colleagues showed that cathepsin G is secreted by neutrophils, binds to the cells’ surface membranes and affects the rearrangement of integrins, an important group of adhesion compounds on the surface of neutrophils.

“The way these integrins rearrange and cluster on the cell surface can send a signal back into the cell that modifies the cell’s behavior, allowing it to do things like secrete inflammatory factors,” Pham said. “The proteases’ ability to affect integrin rearrangement is dependent on their catalytic activity, and that’s an ability that can be taken away from them.”

Pham suspects this class of proteases may make significant contributions to other autoimmune and inflammatory conditions besides arthritis and plans to further investigate this possibility.

Her team is also researching what molecules cathepsin G sticks to and interacts with on the surfaces of neutrophils and other cells.