Identification of novel drug synergy for modulation of endochondral ossification using a combinatorial approach

Osteoarthritis (OA) is a complex whole-joint disease that leads to total joint destruction. Degradation of the cartilage within the joint is a key event that occurs in OA. Importantly, cells within the cartilage are normally in a stable state and help maintain healthy cartilage structure and function. In OA, however, these cells change their behaviour and destroy the cartilage in a process known as endochondral ossification (EO), whilst promoting other disease processes across the joint. This abnormal EO process can occur in any joint within the body resulting in debilitating pain and immobility. In the UK alone, Versus Arthritis UK 2023 reports over 10 million people are affected by OA and arthritis is projected to cost healthcare services £118.6 billion over the next decade. The most recent statistics from the Global Burden of Disease Study 2019 estimate 527.81 million people worldwide are affected by OA more than doubling since 1990, with 40-80% of individuals over the age of 55 presenting with some form of spinal joint degeneration. Factorial design is a combinatorial, algorithmic approach which allows identification of synergistic interactions between drugs that target multiple proteins/pathways and has proven valuable in the development of more effective cancer treatments. This project aims to use factorial design to identify new drug-drug interactions which, when used in combination, display an enhanced ability to reverse diseased cartilage cell behaviour and halt EO to restore healthy joint/disc function in conditions such as OA. It is hoped that identification of these novel drug combinations will function as the blueprint for innovative therapeutic development to improve the quality of life of patients suffering from debilitating degenerative joint conditions.