A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) (ADAMTS5)

ADAMTS5, also known as Aggrecanase-2, is a secreted zinc-dependent metalloproteinase belonging to the ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family [1, 2]. Its primary biological function is the proteolytic cleavage of aggrecan, a critical proteoglycan that provides cartilage with its load-bearing and compressive properties [4, 5]. In healthy tissue, ADAMTS5 activity is tightly regulated by endogenous inhibitors like TIMP3; however, in diseases such as osteoarthritis and rheumatoid arthritis, its overactivity leads to the pathological degradation of the extracellular matrix [1, 16]. This degradation is a hallmark of joint destruction, making ADAMTS5 a high-priority target for the development of disease-modifying osteoarthritis drugs (DMOADs) [3, 7]. Beyond its role in cartilage, ADAMTS5 is involved in versican remodeling during embryonic development, skeletal muscle regeneration, and the migration of T-lymphocytes during viral infections [8, 13]. Therapeutic development has focused on both small molecule inhibitors, such as GLPG1972, and monoclonal antibodies like M6495, which aim to preserve joint integrity by blocking the enzyme's catalytic or substrate-binding domains [1, 14, 17].

Other names

Aggrecanase-2ADAM-TS 5ADAM-TS5ADAMTS11Chondroitin sulfate proteoglycanase

Inhibition of the catalytic activity of ADAMTS5 to prevent the cleavage of aggrecan and other proteoglycans in the extracellular matrix