Micro RNAs as biomarkers in OA

OA is still classified based on changes in joint tissues that are visible on conventional radiographs. This scoring system, however, does not accommodate emerging information about disease mechanisms.

Our proposal aimed to identify and validate miRNAs as future blood biomarkers for monitoring OA pathophysiological processes in cartilage via a 2 step approach:

• Identify miRNA signatures reporting on underlying disease processes and predicting severe OA of the hip and/or knee joint
• Validation and confirmation in additional cohorts across Europe and towards OA in additional joints such as hand OA.

Notably, the results of the pilot study appeared a stepping stone in accessing larger grant money which concurrently established extension of our research question; a high quality miRNA sequencing data set was established in overlapping human samples of cartilage and plasma. Preliminary data analyses showed promising correlation of miRNAs detected in plasma and cartilage, suggesting that circulating miRNA could indeed report on cartilage specific processes. As such the results of the project are bound to deliver biomarkers that reflect diversity in OA pathophysiology with difficult diagnosis.

Up until now strikingly little progress has been made in the development of disease modifying osteoarthritis (OA) drugs. Lack of insight into the diversity of underlying OA pathophysiology and absence of tools to stratify patients based on required mode of action have likely contributed to the diminished progress. For that matter, the pump and prime project “Micro RNAs as Biomarkers in Osteoarthritis” encouraged exploration of a potential new biomarkers source being micro RNAs (miRNA). miRNAs are small RNA molecules regulating (disease) processes in tissues.
Unique is the fact that miRNAs can be secreted as messenger from tissues into the circulation where they were found to reflect ongoing (pathophysiological) conditions. Based on a compelling initial study of Beyer et al. 2014, we hypothesize that miRNAs are valuable molecular biomarkers for predicting underlying OA disease pathophysiology and respective progression. In the pump and prime project we were able to establish isolation of miRNAs from relative small amount of plasma (100 μL) that was of excellent quality and quantity for next generation RNA-sequencing and RT-qPCR. As such significant differences in circulating miRNAs between OA cases and controls were identified.

• R.C. Almeida, Y. Ramos, A. Mahfouz, E. Houtman, N. Lakenberg, G. Kloppenburg, P. Slagboom, R.G. Nelissen, M. Reinders, I. Meulenbelt. Integrative approach uncover microRNA interactome dysregulation in osteoarthritis cartilage. 315 doi.org/10.1016/j.joca.2018.02.353
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• Rodrigo Coutinho de Almeida, Yolande F M Ramos, Ahmed Mahfouz, Wouter den Hollander, Nico Lakenberg, Evelyn Houtman, Marcella van Hoolwerff, H Eka D Suchiman, Alejandro Rodríguez Ruiz, P Eline Slagboom, Hailiang Mei, Szymon M Kiełbasa, Rob G H H Nelissen, Marcel Reinders, Ingrid Meulenbelt. RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage. Ann Rheum Dis 2019;78:270–277. doi.org/10.1136/annrheumdis-2018-213882
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• Ramos, Yolande F. M., Rodrigo Coutinho de Almeida, Nico Lakenberg, Eka Suchiman, Hailiang Mei, Margreet Kloppenburg, Rob G. H. H. Nelissen, and Ingrid Meulenbelt.  Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility—Towards Identification of Applicable Early OA Biomarkers. Biomolecules 11, no. 9: 1356. doi.org/10.3390/biom11091356 
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