Researchers from Rhode Island Hospital and Brown’s School of Engineering have shown in two different animal models that joint fluid lacking in a protein called lubricin fails to adequately lubricate joints. That lack of lubrication leads to increased friction in the joint and eventually to the death of cartilage cells, the research found. The findings, published in the Proceedings of the National Academy of Sciences, help to confirm something researchers have long thought about the root cause of osteoarthritis — that increased friction destroys cartilage, causing joints to fail. Importantly, the work also shows that lubricin protects cartilage and could serve as a means to reduce the risk or even prevent osteoarthritis.
Dr. Gregory Jay, of the Department of Emergency Medicine at Rhode Island Hospital and the School of Engineering at Brown, led the study. He talked with Kevin Stacey about the new findings.
Could you summarize what exactly the research found?
We were able to show experimentally in joints explanted from mice and cows that friction between rubbing cartilage surfaces under a physiologic load is responsible for apoptosis, or programmed cell death of the cells that make up cartilage. Importantly, we found that cell death can be mitigated by the presence of a joint protein called lubricin. Previous studies had reported that lubricin could reduce friction in joints, but none had shown that lubricin played a direct role in protecting cartilage cells.
Cartilage is a mechanical material. It’s meant to absorb strain, to be compressed, and to withstand very high loads. A typical joint can withstand 2,000 pounds per square inch easily. And yet if you overstrain it or if intervening lubricin is not present between cartilage surfaces, then the cells underneath the surface will experience excessive strain — and we show that as a result they undergo programmed cell death.
What do those findings tell us about the role of injury in osteoarthritis?
The findings suggest a mechanism by which major injury or repeated minor injuries to joints can cause osteoarthritis. We know that inflammation and injuries — meniscal tears, ACL tears, gout, inflammatory joint conditions — all down-regulate lubricin. We also know that injuries are an epidemiologic risk factor for OA. So our findings suggest that the loss of lubrication due to the down-regulation of lubricin after injury may be a causal link in the etiology of OA. Once you cause that down-regulation in lubricin, you’re creating a vulnerable period for articular cartilage, we believe.
Are there any potential clinical implications to this?
It would seem to make sense to try to restore lubricin in the period just after an injury to help protect the cartilage and possibly to lessen the prospects for developing OA later in life. Doctors currently inject hyaluronic acid — the viscous component of joint fluid — as part of a therapy called viscosupplementation. But this is generally performed in patients with advanced disease and doesn’t include lubricin. We’re saying it’s worth investigating the use of lubricin in damaged joints before onset of OA.
This study involved both medical researchers and bioengineers. How did those two perspectives inform the work?
This was a collaborative effort between the Departments of Emergency Medicine and Orthopaedics at Rhode Island Hospital and the School of Engineering at Brown.
Like many examples of translational medical research, the work is multidisciplinary and occurs where different fields intersect. Engineers were needed to develop joint pendulum measurement systems ex vivo and measures of cartilage friction in vitro. There was also innovation in testing for biological markers after mechanical testing was done.
What’s the next step for this line of research?
Similar work will be carried out in a large animal model as we work toward a possible orphan drug indication study in patients afflicted with CACP syndrome, a condition in which patients lack lubricin entirely. This will be possible once lubricin is manufactured and can be introduced into joints at risk.