Osteoarthritis (OA) is the last major untreatable rheumatologic disease despite being the most common form of arthritis. Wnt signaling pathway research that is moving toward early stage clinical trials could provide the first disease modifying treatments for OA.
OA affects all three compartments of the joint, synovium, cartilage, and bone. So does Wnt signaling. The line between physiologic activation and pathologic hyperactivation can be a fine one.
“The most common signaling pathway for Wnt proteins to affect bone is the beta catenin pathway,” said Mary Corr, MD, Professor of Medicine at the University of California, San Diego. “But if you activate the beta catenin pathway in cartilage, it can be deleterious. That makes things quite problematic if you are looking for a universal therapeutic for OA.”
Dr. Corr will open the Clinical and Translational Research session The Role of Wnt Signaling in OA, which takes place from 8:30 – 10:00 am Tuesday in Room A411-A412, Building A in the Georgia World Congress Center. The genetics of OA have not changed, she said, but basic discoveries in Wnt proteins and pathways have attracted renewed research attention to OA and significant interest from industry.
One of the basic challenges is the very nature of Wnt signaling. It has different effects in different joint compartments and is also subject to modification from outside cells in the different joint compartments as well as within cells at the DNA level.
“There are a large number of Wnt family members and there are many different types of receptors and co-receptors,” Dr. Corr said. “Then you add on all the potential downstream influences that affect phosphorylation of the signaling pathway as well as the methylation and expression of different gene types. It is a complex system and highly nuanced in regulation.”
Clinicians have long been modifying the Wnt pathway without knowing it. Many common medications affect Wnt signaling, including some of the nonsteroidal agents used to treat OA. Medications commonly used in cardiology, psychiatry, and other specialties also affect Wnt signaling, sometimes giving rise to adverse events.
“Wnt signaling is fundamental to a lot of biological processes, from growth to homeostasis and diseases like cancer,” said Rik Lories, MD, PhD, Professor of Medicine and Director of the Laboratory for Tissue Homeostasis and Disease at KU Leuven, Belgium.
“We can interfere and modify these processes, but it needs to be well thought out,” he continued. “And you need to take into consideration different ways of administering a potential drug as well as how to very precisely target a disease process. But if you can find a technology that is cartilage specific or bone specific, you may have a good chance at making a difference in OA, especially in aging associated disease.”
One approach is to inject agents that modify the Wnt pathway directly into joints affected by OA. Local injection could limit systemic exposure, Dr. Lories noted. It might also be possible to design an agent that preferentially targets cartilage versus synovium or bone, further limiting unwanted effects.
Direct injection could be practical for large joints affected by OA — knees and hips, for example — but would be more difficult for smaller joints such as thumbs and fingers.
That is if OA of the thumb and fingers is even the same disease. For many people, it is not. Thumb disease is very common and is most often associated with overuse. Finger OA is less common and strongly linked with inflammatory processes and hormonal status.
“OA is the outcome of many different processes,” he said. “You can easily imaging that having knee OA in a former athlete who blew up his knee at 25 is different from the OA that develops in a very overweight person at age 65. And different again for someone who has no risk factors except genetics and develops OA much later in life. This symposium is setting the stage for the next phase, which we all hope will be treatment for the underlying disease in OA, not just treating pain.”