A major international study suggests that osteoarthritis (OA) of the knee is a single disease with common core underlying biological pathways, rather than a collection of distinct molecular disease subtypes.
The Synovial fluid To detect Endotypes by Unbiased Proteomics in OA (STEpUP OA) study, led by researchers from the Kennedy Institute of Rheumatology at the University of Oxford, is the largest molecular analysis of osteoarthritis tissue to date.
Researchers analysed synovial fluid from more than 1,300 people with established knee OA, using a cutting-edge proteomics platform that measured more than 7,000 proteins per sample.
Each sample was linked to details about the patient, including age, biological sex and body mass index. Analyses of these characteristics revealed that although OA has a single molecular fingerprint, there is biological variation influenced by factors such as obesity, sex and age.
The researchers found that several biological processes – angiogenesis, complement and coagulation – were more prominent when patients were grouped according to these clinical characteristics.
Complement and coagulation findings were linked to C-reactive protein (CRP), suggesting that these processes were related to the level of inflammation patients were experiencing, and were more common in obese patients, while angiogenesis and coagulation were more evident in male patients.
Study participants with obesity had additional inflammatory signals, which were distinct from the immune cell inflammation seen in rheumatoid arthritis and other diseases. Instead, investigators determined they indicated a tissue-injury response that was most likely linked to mechanical stress.
Overall the researchers identified the dominant biological pathway across all patients as Epithelial Mesenchymal Transition (EMT), reflecting active tissue remodelling.
“For decades, the field has debated whether OA is really a group of separate diseases, perhaps explaining why so many clinical trials have failed,” said Professor Tonia Vincent, the study’s lead investigator and Director of the Arthritis UK Centre for OA Pathogenesis at the Kennedy Institute.
“We revealed no evidence of distinct disease subtypes, instead, we’ve demonstrated that at the molecular level OA is a single disease with a common set of “core” pathways, mostly related to tissue injury and repair.”
These findings help explain why patients respond differently to therapies and help researchers “design more targeted clinical trials” for OA, which currently has no approved disease-modifying therapies.
At the same time, the investigators found weaker links between the biological pathways and the knee pain patients reported feeling, suggesting that the biology doesn’t clearly map the pain experience.
The full results of the study are published in Nature Communications [link here].
Open dataset
The STEpUP OA dataset is available to researchers, with the expectation that scientists can use it to explore key biological pathways and better design clinical trials.
“Understanding the biology of osteoarthritis will help us develop better, more personalised treatments for people with osteoarthritis,” said Professor Lucy Donaldson, Director of Research at Arthritis UK.
“People experience OA differently. We know for example that perimenopausal women face higher risk, and that some people see their symptoms progress far more quickly than others,” she added. “Understanding the mechanism of OA is a crucial step towards understanding why the condition varies so much between individuals.”
The Oxford researchers collaborated with Imperial College London, University of Nottingham, University of Cambridge, Lund University, Maastricht University, Schroeder Arthritis Institute in Toronto, and Western University.