Calling the Wrong Number

The term “aberrant cytokine signaling” is a mouthful, but accurately describes the disease process after some sports-related injuries. Here is what it means: 

Biologic Responses to Sports Injuries

You injure a joint, knee, shoulder, or ankle. Inflammation occurs. This means that new blood is brought to the site, from broken blood vessels and fluids released by local cells. This biologic response also produces chemokines: small proteins that act as signaling factors, calling in a range of responses that are (usually) helpful in the healing process. For example, specific factors induce the body’s stem cells to divide and rush to the site of injury. Other cells—now called medicinal signaling cells—direct the healing response by reducing scar formation, stimulating cell proliferation, and modifying the immune response, among other behaviors. 

Usually, the body does a balancing act: It initiates a response that includes a mix of factors, then shuts down that response with a mix of other factors. Sometimes, though, the wrong signal is sent—or the same signal continues to be sent. For instance, if certain collagen-stimulating factors are continuously signaled, an overproduction of collagen can occur. This appears most commonly as scar formation or on the skin surface as a keloid. In other cases, factors that are anti-inflammatory at low concentrations become inflammatory when released at high concentrations, leading to swollen joints. The factors that break down scars to modulate healing can also break down the normal articular cartilage surface of the joint, leading to arthritis. 

Much of today’s research focuses on how to get just the right amount of signal produced. Unfortunately for both the FDA and for patients, almost all such signaling in the human body is done with a variety of proteins. Like instruments in a symphony, they interact to balance each other. Very rarely is there a soloist. So for the FDA—a regulatory body that wants to know the specific action of a specific drug at a specific dose—the field of regenerative biology is a nightmare. 

The best example of why this is so is PRP, platelet-rich plasma. PRP is derived from the platelets in the blood of patients. By spinning the blood (not the patient!) in a centrifuge, the platelets are isolated. Within these platelets are alpha granules (small packets that contain a wide array of factors) and a collection of even smaller packets called exosomes that carry particles of active messenger RNA. 

One problem with getting the FDA approval is that PRP varies from patient to patient, and even from morning to nighttime. Standardizing PRP has been impossible—yet PRP from a patient has highly potent regenerative medicine abilities and is now, in combination with the lubricant hyaluronic acid, our first-line treatment in most sports injuries and arthritis conditions. It is the chicken soup of human biologic therapies, appearing to send all the right signals to assist in healing. 

When the wrong signals are active in a patient, PRP can help change the message. But if we hope to advance the field, and find more potent and specific therapies, we need to get to the point where we can test—and the FDA can approve—biology’s version of Grandma’s chicken soup.  

Medically authored by
Kevin R. Stone, MD
Orthopaedic surgeon, clinician, scientist, inventor, and founder of multiple companies. Dr. Stone was trained at Harvard University in internal medicine and orthopaedic surgery and at Stanford University in general surgery.