Clues in Gene Expression

In research funded by the Arthritis Foundation, Dr. Loeser and Wake Forest colleagues Jacquelyn Fetrow, PhD, Michael Callahan, PhD, and Cristin Ferguson, MD, along with Cathy Carlson, DVM, PhD, at the University of Minnesota, are studying aging in knee joints with a mouse model of post-traumatic osteoarthritis. They want to find out which genes are turned on and off as OA takes hold in young versus old mice. Examining the pattern of this gene expression may show the key genes responsible for development of OA in aging.

The researchers used mice in two age groups: 12 weeks (an age comparable to human teenagers), and 12 months (an age comparable to people in their 40s or 50s), when OA starts to develop.

The group used experimental surgery that mimics a meniscus injury (damage to the crescent shaped cartilage that cushions the knee) and starts the knee on a path to post-traumatic OA. People under age 30 who suffer a meniscus injury take twice as long to develop OA than if the same injury occurred in people over age 30.  In the mouse model, OA starts to develop in about 8 weeks.

Since OA affects the entire joint, Dr. Loeser and Dr. Fetrow tried something unique. Most researchers study only the cartilage in this model. Loeser’s team sampled tissue in the entire joint, the meniscus, the joint lining, and ligaments and tendons, as well as cartilage and bone.

The team discovered that, as in people, the younger mice developed less severe OA than the older mice at same time point after surgery. The old mice had twice as severe OA as the young mice.

The difference may be explained in the genes. In all, the team found 493 genes that were either switched on or switched off in the two age groups. Only 55 genes were similar between the two age groups.   In the 438 genes that differed between the age groups, the older mice had a lot more genes turned on. In the younger mice, more genes were turned off.

“It shows how aging can really affect gene expression,” says Dr. Loeser. The researchers are now aiming to identify the most important genes to see which are key in development of OA as those would be targets for therapy.

“The significance of this project is that we will be able to identify the origins of the disease, from the gene expression data, from the very earliest time points.  That is something you cannot do with human tissue; by the time you can access human tissue, the disease is late stage.  That means that we have the potential to identify the mechanistic origins of osteoarthritis from the very start of the disease, which could enable us to identify the disease in humans earlier than we can currently and to possibly identify interventions at earlier stages than currently possible,” says Dr. Fetrow.