Research topic: Investigating the molecular pathways activated by meniscal injury that can lead to meniscal degeneration and osteoarthritis
Research results: Determining if the hypoxia-induced factor (HIF) pathway and NF-κB interactions are implicated in the development of osteoarthritis in the meniscus and if they could be the basis for developing inhibitors that could be locally administered to prevent, attenuate, or possibly reverse degenerative changes
Patient care application of results: Development of inhibitors that could be locally administered to prevent, attenuate, or possibly reverse meniscus degeneration
Simplified patient care application: Prevention of the degenerative changes that lead to osteoarthritis after a meniscus injury
Must osteoarthritis always follow a meniscal injury?
OREF grant recipient works to eliminate link between injury and chronic pain
Knee pain is responsible for about a third of all doctor visits for muscle and bone pain. In fact, more than half of all athletes endure that pain every year, along with sports enthusiasts and the aging population. One of the major reasons for knee pain is an injury to the meniscus, which is almost always followed by osteoarthritis (OA). But the molecular mechanisms by which an injury to the meniscus causes it to degenerate to the point where an OA diagnosis is made are unclear.
Austin V. Stone, MD, PhD, is a resident physician/scientist in the department of Orthopaedic Surgery at Wake Forest University Health Sciences in Winston-Salem, N. C. With a 2011 resident clinician scientist training grant from the Orthopaedic Research and Education Foundation (OREF), Dr. Stone aimed to define the molecular pathways activated by meniscal injury that result in meniscal degeneration and contribute to the development of OA.
“The hypoxia-induced factor (HIF) pathway is implicated in the development of osteoarthritis,” said Dr. Stone. “That HIF pathway and NF-κB interactions could represent therapeutic targets for the treatment of osteoarthritis,” Dr. Stone said.
Dr. Stone pointed out that current treatment options for meniscus injury are limited to attempted surgical repair, partial resection, or non-operative rehabilitation. Identification of HIF-2α and NF-κB control of catabolic gene expression in the meniscus would provide the basis for developing a highly specific HIF-2α or NF-κB pathway inhibitor that could be locally administered to prevent, attenuate, or possibly reverse degenerative changes. Additionally, because the HIF pathway is involved in meniscus cell phenotype differentiation, it may carry implications for tissue engineering.
Looking at the joint as a whole
The basic science component has direct applicability to Dr. Stone’s clinical research interests in the orthopaedic fields of pediatrics, trauma, osteoarthritis, and sports medicine. “This project builds on my research experience previously funded by OREF that explored juvenile osteochondritis dissecans, which is linked to the development of osteoarthritis.”
Dr. Stone explained that osteoarthritis remains an enigma in joint disease, but it is increasingly apparent that the disease process is a function of the whole joint and not solely the articular cartilage. “I believe that the joint should be treated as an organ,” he said, “Instead of looking at the tissues individually, we should look at them as a whole. It’s not just a cartilage problem that leads to osteoarthritis or a bone problem causing the collapse in osteochondritis dissecans. It’s a dynamic among multiple tissues.”
By approaching the joint as an organ, Dr. Stone believes more effective therapeutic interventions may be developed to mitigate early pathway aberrations leading to joint degeneration.
“We want to understand the biologic interruptions that happen inside the joint very early on that can lead to that disease process and that may ultimately result in the need for a total joint replacement,” he said. “Instead of looking at the end point, we’re looking at the very early beginning, before patients even know that they’re having disease progression. We’re filling a void in research by better understanding basic meniscus biology. And in the process, we’re gaining a much better understanding of the difference in the pathobiology of the meniscus.”
Dr. Stone and his research team looked at both healthy meniscus specimens as well as specimens that were discarded during total joint surgery. The research team applied microscopy to determine cell morphology. They also stained for specific intracellular components to observe any cytoskeletal structure changes.
In addition, the research team created a monolayer culture from which they harvested cell media to determine what excretions those cells put into the extracellular matrix or the synovial fluid in the joint. The single layer monoculture also allowed them to see the intracellular proteins.
“We’ve also looked at gene expression. Our goal was to determine that a protein is being expressed at the genetic level, that it is functioning at the protein level and that it is somehow changing what happens outside of the cell.
In a complementary study, the research team looked at cartilage to learn how the meniscus behaves differently and similarly to it. They found that treating cartilage with inflammatory mediators similar to those found in an injured meniscus joint helped them to understand the protein expression and gene changes in primary monolayer culture.
Funding for new investigators
Dr. Stone said he appreciates his OREF funding because he’s aware of how few grants are available for residents and new investigators without substantial preliminary data.
“OREF has several of these grants that allow researchers to develop some early data, which can lead to much larger grants. Or, depending upon the nature of the grant, perhaps some additional partnerships will be available down the road for larger clinical studies or more expanded basic science studies.”
Findings from these grants, Dr. Stone said, have potential to bring what’s learned from the bench to the bedside. “You have to start with a clinical question and then look at it from the bench side. This grant enables you to do that. It’s the first step in taking new treatment options back to the patient.”