BIO-SCAVENGING: A PROMISING THERAPEUTIC APPROACH TO ADDRESS CARTILAGE ASSOCIATED DISEASES

Abstract

Abstract According to the Global Burden Diseases (GBD) report of 2022, ~500 million people suffer from degenerative and inflammatory musculoskeletal joint disorders alone. The musculoskeletal joint disorders are the primary cause of life-time disability in many cases. In such individuals, inflammation and severe pain is manifested in the joints like knees, hands, feet, hips and spine. The degeneration of cartilage and the underlying bone leads to chronic inflammatory diseases of joints such as osteoarthritis (OA) and rheumatic arthritis (RA). Articular cartilage (AC) is a specialized type of connective tissue that covers the ends of bones in joints, providing a smooth, lubricated surface that allows for frictionless movement of the joint. AC possesses limited ability for natural healing and regeneration due to its lack of blood vessels. Consequently, safeguarding and maintaining the health of AC is crucial for the overall well-being of the joints. Protecting AC from further damage is a significant challenge for patients, surgeons and physical therapists. Joint injuries or its overuse can accelerate the breakdown of cartilage leading to OA, a degenerative inflammatory joint disease. OA is characterized by an increase in pro-inflammatory markers such as Nitric oxide (NO), IL-1β and TNF-α. Typically, in acute inflammatory conditions, a series of cellular and molecular events work together to minimize the damage or infection. However, when acute inflammation is not properly controlled, it can transit into a chronic state, which manifests as chronic inflammatory diseases. This chronic inflammation can damage the joints contributing to OA progression. Elevated levels of inflammatory markers lead to an increase in matrix metalloproteases (MMPs), which in turn causes cartilage degeneration. This degeneration subsequently leads to subchondral bone (SB) damage and subsequently to joint instability. The existing pharmaceutical approaches to treat OA includes drugs that mitigate pain and inflammation. However, there is no approved drug that can prevent/modify the damage to the articular cartilage. Understanding the current scenario, we proposed to develop therapeutic approaches that prevent the progression of cartilage degeneration. Scavengers are molecules that play a central role in removing, neutralizing, or detoxifying harmful substances in the body. These substances can include free radicals like nitric oxide (NO), superoxide, hydrogen peroxide, reactive oxygen species (ROS), reactive nitrogen XXIspecies (RNS), toxins, pathogens or other harmful molecules. Scavengers also play an important role in the body’s defence mechanism against infections. Scavengers can protect cells and tissues from inflammation-induced damage. In this regard, my thesis focuses on various scavenging approaches that can be used to prevent cartilage degeneration. 1) Chapter 1, explores the therapeutic potential of scavenging nitric oxide (NO) to mitigate inflammation and matrix degradation using synthesized Urea-based push-pull chromophore molecules. 2) In Chapter 2, the primary focus was to scavenge MMP-13, a major matrix metalloprotease involved in OA, using a hydrogel carrier system to deliver a specific MMP- 13 blocker to prevent cartilage degeneration. 3) Chapter 3, focuses on conducting a comprehensive screening of various curcumin metabolites to identify their potential to bind and scavenge metalloproteases specifically collagenases (MMP-1, MMP-8 and MMP-13). 4) Chapter 4, deals with the development of a potent and compatible collagenases blocker to prevent cartilage degeneration. Based on the previous computational results, I have selected, synthesized and checked the efficacy of Curcumin Monoglucuronide (CMG), a stable curcumin metabolite to bind to collagenases and prevent cartilage degeneration. Overall, this thesis demonstrates the potential of these scavenging approaches for preventing cartilage degeneration. These approaches can be beneficial in mitigating further cartilage damage in cartilage associated inflammatory diseases like osteoarthritis and rheumatoid arthritis.