By UHN Research Communications
A new collaborative study from UHN's Schroeder Arthritis Institute and Women's College Hospital has provided insight into a condition known as post-traumatic osteoarthritis (PTOA) and how it occurs following injury to the anterior cruciate ligament (ACL).
Researchers have identified changes in molecules called microRNAs (miRNAs) and metabolites following ACL injury and subsequent reconstruction surgery.
"Injury to the ACL, often caused by sport or other physical activity, can lead to PTOA within five to 10 years — a condition that can result in joint pain and stiffness over time," says Dr. Darrell Ogilvie-Harris, clinician investigator at Schroeder Arthritis Institute and co-senior author of the study.
"ACL reconstruction is a common procedure after knee injuries, but it is not able to prevent the development of PTOA," adds Dr. Ogilvie-Harris, who is also a professor in the Department of Surgery at the University of Toronto (U of T).
Various molecular alterations occur within the joint after injury.
"Small molecules such as microRNAs (miRNAS, molecules that play an important role in gene expression) and metabolites (molecules that arise as a by-product of various cellular and metabolic processes) are now recognized as being involved in OA pathogenesis," says Dr. Mohit Kapoor, Senior Scientist at the Schroeder Arthritis Institute and co-senior author of the study.
"However, knowledge of the molecular alterations occurring in the early stages post-ACL reconstruction is limited," adds Dr. Kapoor, who is also a Tier 1 Canada Research Chair in Mechanisms of Joint Degeneration and a professor in the Departments of Surgery and Laboratory Medicine and Pathobiology at the U of T.
Researchers sought to understand the molecular pathways involved in the development of PTOA.
"By understanding how miRNAs and metabolites change shortly after surgery, we can learn more about why PTOA occurs," says Dr. Amit Sandhu, postdoctoral researcher in Dr. Kapoor's lab. "To do this, we used advanced sequencing and molecular analysis techniques to examine blood samples and see how miRNAs and metabolites change in the first two to six weeks after ACL surgery."
"Among 43 patients who had ACL reconstruction, we found that levels of 46 different miRNAs and 13 metabolites increased from pre-surgery to two weeks post-surgery, while six other metabolites decreased in that time," says Katrina Hueniken, biostatistician in Dr. Kapoor's lab and co-first author of the study.
Interestingly, the team also examined the differences between males and females to determine whether there is differential expression that may influence PTOA's natural trajectory.
"When comparing males to females, we found that one specific miRNA was higher in females post-surgery, with several other miRNAs and metabolite levels differing between females and males," says Dr. Tim Dwyer, orthopaedic surgeon at Women's College Hospital and Mount Sinai Hospital, associate professor of surgery at U of T and co-senior author. "This suggests differences in metabolic responses between females and males that may impact the development of PTOA after ACL injury and post-surgery."
In addition, the team used a computational method to see if the miRNAs and metabolites identified were associated with common genes and signalling pathways to further elucidate how these molecules may be working. This analysis revealed key signalling pathways for different post-surgical time-points and in females versus males.
Researchers detected enrichment for components of nervous system, signal transduction, and amino acid transporter pathways.
"The signature of miRNAs and metabolites in patients undergoing ACL reconstruction that we uncovered could provide insights into the molecular pathways involved in PTOA and promising targets for further investigation," says Dr. Jas Chahal, Division Head of Orthopaedic Surgery at Women's College Hospital, associate professor at U of T and co-senior author of the study. "Further studies are needed to fully understand how these factors play a role."
This study is funded by UHN Foundation, the Tony and Shari Fell Platinum Chair in Arthritis Research, the Natural Sciences Research Council of Canada, the Canada Foundation for Innovation, IBM and the Ian Lawson van Toch Fund.
