Identification and validation of clinically useful biomarkers for diagnosis and monitoring of osteoarthritis

Abstract

Osteoarthritis (OA) affects more than 500 million people globally. Early detection of OA is crucial for establishing effective therapeutics and reducing progression risk, but no applicable clinical biomarkers are available. The project's main aim is to identify the ‘best’ qualified and clinically effective biomarkers for knee OA by utilising data from one of the largest and best-characterized OA cohorts: Osteoarthritis Initiative (OAI), where radiographic, clinical, and molecular biomarkers were followed up over ten years. I evaluated the association of baseline biomarkers with clinical and radiographic outcomes using several regression models. The cross-sectional study revealed that 4 out of 19 biomarkers were the ‘best’ biomarkers for OA. Of these four biomarkers, uCTXII showed the strongest and most consistent associations with clinical symptoms of OA (WOMAC pain: OR 95% CI 1.0138 (1.0023, 1.0253) as well as radiographic evidence of joint damage (K&L grade: OR 95% CI:1.0607 (1.0231, 1.0996). The association of biomarkers with OA progression in this cohort showed that there were correlated with progression and were informative for identifying subgroups at risk of OA progression: uCTXII(OR 95% CI: 1.0389(1.0016, 1.0774)), sPIIANP(OR 95% CI: 1.00198(1.00046, 1.00349)), sColl2-1 NO2(OR 95%CI: 1.72176(1.22544, 2.4191) and sCS846(OR 95% CI: 1.00386(1.00022,1.00752)). An independent validation study in a Bristol Cohort supported many of the major findings and revealed different types of biomarkers behave differently in OA. I developed a highly sensitive assay and investigated the association of C3f (a novel biomarker) with radiographic and clinical outcomes in both Bristol and OAI cohort. C3f was associated with K&L grade(OR 95% CI: 0.9922 0.9868, 0.9976)) and JSN medial(OR 95% CI: 0.9914(0.986, 0.9968)) and was increased in the late stages of OA. However, further studies on different OA joints and phenotypes are needed to validate the value of C3f as a useful marker.

This work proposes that uCTXII is a clinically useful biomarker and sufficiently validated for drug development and clinical trial use. Likewise, combination of biomarkers would be informative for diagnosing and monitoring OA.

Date of Award	6 Dec 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Mohammed Sharif (Supervisor) & Andy Judge (Supervisor)