The document discusses whether osteoarthritis (OA) should be considered one disease or many, as there is evidence that OA is a heterogeneous condition influenced by different risk factors, molecular pathways, and disease mechanisms. Genome-wide association studies have linked over 100 genetic loci to OA risk, indicating different pathways can contribute to OA in different patients. While some genes have been shown to play different roles in different mouse models of OA, together this suggests OA may comprise distinct subtypes that could require targeted treatment approaches.
5. With this endorsement, an anonymous colleague suggested
there is really no need for a debate any more?
@littlecb5001, personal communication
6. • OA is highly heterogeneous
• This heterogeneity is linked to differences in disease
mechanisms
• Which might require different treatment strategies
7. Loose association between
structure and symptoms
Different rates of progression
Large variety of risk factors
(age, obesity, injury, sex,
occupation, genetics…)
OA is heterogeneous
8. Prieto-Alhambra et al ARD 2014
Hunter & Bierma-Zeinstra Lancet 2019
OA incidence
by joint and
sex
9. Wallace et al PNAS 2017
OA prevalence changes over time
15. So OA is heterogeneous
So what?? Does this mean anything?
Are these differences caused by different
underlying mechanisms that can be differentially
targeted?
16.
17. Genome-wide association studies in OA
• Close to 100 different loci have been linked to risk of OA
• The affected genes encode many different pathways and functions
• ECM, transcription and epigenetics, Wnt, TGFbeta, retinoic acid..
Different pathways contribute to OA in different patients
18. 2016-10-16, 8:53 AMPLOS Genetics: Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
Abstract
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for
osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness,
one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width
(mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227
individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10 ) SNPs annotated to
four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis
fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA
(rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and
SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse
Published: October 4, 2016 http://dx.doi.org/10.1371/journal.pgen.1006260
Novel Genetic Variantsfor Cartilage Thicknessand Hip
Osteoarthritis
Martha C. Castaño-Betancourt , Dan S. Evans , Yolande F. M. Ramos , Cindy G. Boer , Sarah Metrustry, Youfang Liu,
Wouter den Hollander, Jeroen van Rooij, Virginia B. Kraus, Michelle S. Yau, Braxton D. Mitchell, Kenneth Muir, Albert Hofman,
Michael Doherty, Sally Doherty, Weiya Zhang, Robert Kraaij, Fernando Rivadeneira, Elizabeth Barrett-Connor,
Rose A. Maciewicz, Nigel Arden, Rob G. H. H. Nelissen, Margreet Kloppenburg, Joanne M. Jordan, Michael C. Nevitt,
Eline P. Slagboom, Deborah J. Hart, Floris Lafeber, Unnur Styrkarsdottir, Eleftheria Zeggini, Evangelos Evangelou,
Tim D. Spector, Andre G. Uitterlinden, Nancy E. Lane , Ingrid Meulenbelt , Ana M. Valdes , Joyce B. J. van Meurs
−8
Appleton et al A&R 2007b
A link between TGFA and human OA
19. Tgfa KO mice are protected from post-traumatic OA
but not from aging-associated OA
Control
Post-traumatic
Aging
Tgfa KO
Usmani et al Scientific Reports 2016
23. Wrap up
• Human GWAS studies suggest that de-regulation of many
different molecular pathways can predispose to OA
• Mouse studies show that genes can play different roles in
different models of OA
• different molecular pathways can drive different OA
phenotypes and might require different treatments
24. Thank you Dr. Tom Appleton
Dr. Trevor Birmingham
Dr. Chris Little
Dr. Tonia Vincent
Toronto Police Service
25. Berenbaum et al Nature Rev Rheum 2018
OA as a mismatch disease?