OP0111 PLASMA PROTEOMICS IDENTIFIES CRTAC1 AS BIOMARKER FOR OSTEOARTHRITIS SEVERITY AND PROGRESSION
Authors: Szilagyi I. , Vallerga C. , Waarsing J. H. , Schiphof D. , Bierma-Zeinstra S. M. A. , Van Meurs J. 
Published: May 2021

Background:

Accurate biomarkers for diagnosis and prediction of osteoarthritis (OA) are needed. In addition, biomarkers have the potential to serve as a measure of the different pathological processes underlying OA. Here, we report on a proteomics screen targeted at two important pathways thought to underlie the etiology of OA: the inflammation and metabolic pathways.

Objectives:

The aim of this study was to identify a robust biomarker for OA severity and progression.

Methods:

We used data from the Rotterdam Study, a population based prospective study with participants aged 45 and older. The participants in this study underwent blood measurement at baseline and radiographic measurements at baseline as well as after a mean follow-up time of 5 years. We measured 184 proteins (inflammation and cardiometabolic panel) in plasma from 3,517 participants in the Rotterdam Study using the Olink platform.

We estimated the association for all available proteomic biomarkers with OA in knee, hip and hand in 2 ways: 1) Cross-sectionally in all joints, where we analyzed severity of OA by adding up KL-scores of both joints (knee and hip OA), and all joints of the left and right hand (total amount of joints=30); 2) Longitudinally in Knee and Hip, defining cases of progression of OA as an increase with at least 1 unit in KL-grade per person, excluding progressing from KL0 to KL1. We analyzed the relationship with multivariate regression models using generalized linear models with binomial link function. In model 1 we adjusted for age, sex and cell counts, in model 2 we additionally adjusted for BMI. We report effect estimate(beta) per standard deviation (SD) change in protein levels with 95% Confidence Interval (CI) and nominal p-value (significance level<0.05) for each protein. All statistical analyses were performed in R version 3.5.2.

Results:

We found in total 56 proteins that were significantly associated with one or more OA-outcomes at nominal level. Figure 1 illustrates the 19 significant associations for severity of hand OA ordered by significance level (most significant at top). We observed a very robust association between the level of circulating Cartilage acidic protein 1 (CRTAC1) and severity of OA in the knee (β=0.16, 95%CI 0.09-0.23, p=0.000013, FDR-corrected P:0.0011) hand (β=0.086, 95%CI 0.03-0.14, p=0.00085, FDR-corrected P: 0.0252), while a similar trend was seen in hip (β=0.08, 95%CI -0.02-0.18, p=0.12), although power in hip was limited in our study. The association with CRTAC1was also found for progression in knee (β=0.21, 95%CI 0.03-0.36, p=0.0156, FDR-corrected P>0.2) and hip (β=0.18, 95%CI -0.01-0.38, p=0.0624, FDR-corrected P>0.9). These associations were independent of BMI. Among the findings were several other promising biomarkers, e.g. MMP-10, which we observed to be associated with severity of hand OA (β=-0.09, 95%CI -0.15- -0.04, p=0. 00067, FDR-corrected P:0.0383) and progression of knee OA (β=-0.24, 95%CI -0.42- -0.06, p=0.0073, FDR-corrected P>0.1). Additionally, COMP, a well-known biomarker for OA, was also found significant for OA severity in hand (β=0.10, 95%CI 0.05-0.16, p<0.001, FDR-corrected P:0.0043) and knee (β=0.09, 95%CI 0.02-0.17, p=0.01, FDR-corrected P>0.2).

Conclusion:

We identified the CRTAC1 protein as a robust, promising biomarker for osteoarthritis severity and progression. This protein is a glycosylated extracellular matrix protein that is found in the interterritorial matrix of articular deep zone cartilage. This protein can also be used to distinguish chondrocytes from osteoblasts and mesenchymal stem cells in culture. This suggests that CRTAC1-levels reflects a cartilage-specific process in the joint. Such a biomarker might be useful for targeting the right patients for clinical trials and designing novel therapies for OA.

Disclosure of Interests:

Ingrid Szilagyi: None declared, Costanza Vallerga: None declared, J.H. Waarsing: None declared, Dieuwke Schiphof: None declared, S.M.A. Bierma-Zeinstra Consultant of: Pfizer, one day consultancy, Joyce Van Meurs: None declared