Large-scale molecular endotype discovery in synovial fluid reveals osteoarthritis as a single biological continuum
Abstract
Abstract Knee osteoarthritis affects 40% of people during their lifetime, significantly impacting societies worldwide. Its molecular pathogenesis remains poorly understood and variable clinical phenotypes suggest it may be more than one disease. We established S ynovial fluid T o detect E ndoty p es by U nbiased P roteomics in OA (STEpUP OA) to search for molecular endotypes in knee OA synovial fluid, and to reveal key pathobiological pathways across 1361 individuals with knee OA. Using unsupervised clustering, a single cluster representing a biological continuum is observed, primarily driven by “Epithelial Mesenchymal Transition”. Distinct molecular endotypes are not detected. “Angiogenesis”, “Complement” and “Coagulation” are enriched for after stratification by clinical phenotype (obesity status, biological sex). Complement and coagulation are associated with the inflammatory marker, C-reactive protein. Associations with patient-reported knee pain are weaker. These findings support knee OA as a biological continuum, identify common and phenotype-enriched targetable pathways, and a rationale for stratification in clinical trial design.
Article Details
Authors (79)
T. A. Perry
Y. Deng
P. A. Hulley
R. A. Maciewicz
J. Mitchelmore
S. Larsson
J. Gogain
S. Brachat
A. Struglics
C. T. Appleton
S. Kluzek
N. K. Arden
D. Felson
L. Bondi
M. Kapoor
L. S. Lohmander
T. J. Welting
D. A. Walsh
A. M. Valdes
Luke Jostins-Dean
Fiona E. Watt
B. D. M. Tom
T. L. Vincent
Thomas A. Perry
Yun Deng
Center for Computational Biology
Philippa A. Hulley
Rose M. Maciewicz
Stefan Kluzek
Nigel K. Arden
Tonia L. Vincent
Vicky Batchelor
Jennifer Mackay-Alderson
Gretchen Brewer
Brian Marsden
Andrew J. Price
Megan Goff
Vinod Kumar
James Tey
Tamas Szommer
Joanna Mitchelmore
Sophie Brachat
Juerg Gasser
Lori Jennings
Staffan Larsson
André Struglics
L. Stefan Lohmander
Joe Gogain
Darryl Perry
Anna Mitchel
Ela Zepko
C. Thomas Appleton
Trevor B. Birmingham
J. Daniel Klapak
David Felson
Laura Bondi
Brian D. M. Tom
Mohit Kapoor
Rajiv Gandhi
Anthony Perruccio
Y. Raja Rampersaud
Kim Perry
Tim J. Welting
Pieter Emans
Tim Boymans
Liesbeth Jutten
Marjolein Caron
Guus van den Akker
David A. Walsh
Ana M. Valdes
Michael Doherty
Vasileios Georgopoulos
Artemis Papadaki
Andrew Williams
Tim Hardingham
Sarah Kennedy
Jeymi Tambiah
Devis Galesso
Nicola Giordan
Waqar Ali