A research team at the University of Massachusetts Medical School in Worcester has made important findings regarding bone erosion and formation that may lead to better treatment options for people impacted by rheumatoid arthritis (RA).
Ellen Gravallese, MD, rheumatology division chief and professor of medicine and cell biology at the University of Massachusetts, received a two-year disease-targeted research grant from the ACR Research and Education Foundation in 2008 to study how osteoclasts and osteoblasts affect bone erosion and healing in RA.
Her lab had previously published studies identifying osteoclasts as cell types involved in bone erosion in patients with RA. In addition, her team had identified receptor activator of NF-κB ligand in synovial tissue as an important factor driving osteoclast differentiation in arthritis. With the clinical use of disease-modifying and biologic agents, rheumatologists observed that the osteoclast-mediated erosive process could be retarded or even arrested. However, there was little evidence of new bone formation. “There was no further erosion, but it’s rare to see bone repair,” says Dr. Gravallese. “In normal bone remodeling, osteoblasts would fill in bone that had been lost or removed.”
With the assistance of the REF grant, Dr. Gravallese’s team decided to focus more closely on osteoblasts. Dr. Gravallese poses the research as a simple question: Once there has been erosion introduced by RA, is it possible to heal the bone?
“What this work suggests is that when we don’t see bone healing in RA, there may still be inflammation present, even though we don’t recognize it clinically.”
—Ellen Gravallese, MD
Her team tested this question by using the serum transfer arthritis model. Mice were injected with arthritogenic serum, leading to inflammation and bone erosion. After the injections were stopped, the inflammation would begin to disappear. But would the bones heal?
“When inflammation was at its peak, very little bone was being laid down,” says Dr. Gravallese. “But as the inflammation resolved, we began to see bone formation at prior inflammation–bone interfaces.”
Peak inflammation occurred around Day 10 after the initial serum transfer. By Day 21, mature osteoblasts began to enter the site of erosion. By Day 28, bone formation was observed, and the bone continued to repair over the next several weeks. “What we found,” says Dr. Gravallese, “is that as inflammation resolves, you see that bone can be formed at that site. What this work suggests is that when we don’t see bone healing in RA, there may still be inflammation present, even though we don’t recognize it clinically.”
Dr. Gravallese says there may be other factors that keep the bone from healing. For instance, the chronic nature of RA may cause a permanent change in the marrow environment, or may prevent osteoblasts from getting into the site.
To study the process of osteoblast differentiation, Dr. Gravallese’s team also looked at synovial tissues in the serum transfer model for factors that might be regulating bone formation. They found that when inflammation is at its peak, there is expression of inhibitors of the Wnt signaling pathway (the network of proteins involved in the differentiation and positive function of osteoblasts). As the inflammation decreases, expression of the inhibiting factors also begins to decrease. “Inflammation seems to be regulating expression of factors that affect Wnt signaling,” says Dr. Gravallese.
This research may have far-reaching implications, because treatments that are able to more effectively control inflammation could help trigger bone formation in patients with RA. Dr. Gravallese presented her findings in January at the Keystone Symposia Meeting on Rheumatoid Arthritis, which was organized with the support of the REF.
She credits the Within Our Reach: Finding a Cure for Rheumatoid Arthritis grant she received from the REF as a key factor in the research process. “The grant allowed us to go in a completely new direction, focusing on osteoblasts and the process of bone formation. It also allowed us to generate quite a bit of preliminary data,” says Dr. Gravallese, “and we were able to obtain new funding based on these data.”