ADAMTS5

ADAMTS5 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5), also termed aggrecanase-2, is a zinc-dependent extracellular protease primarily involved in cartilage degradation through cleavage of aggrecan, a key component of the extracellular matrix. It operates via its catalytic domain and ancillary thrombospondin motifs, modulating interactions within the TGF-β and NF-κB signaling pathways. This enzyme is tightly regulated by cytokines such as IL-1β and TNF-α, which drive its overexpression in inflammatory conditions. Its activity is counterbalanced by endogenous inhibitors like TIMP-3, maintaining tissue homeostasis. Dysregulation of ADAMTS5 is strongly implicated in osteoarthritis progression, where excessive aggrecanolysis disrupts cartilage integrity, accelerating joint degeneration.
Current therapeutic strategies targeting ADAMTS5 focus on selective inhibition to mitigate cartilage damage without impairing physiological metalloproteinase functions. Small-molecule inhibitors (e.g., GLPG1972) and monoclonal antibodies have shown efficacy in preclinical models, though none have advanced beyond Phase II clinical trials due to challenges in specificity and off-target effects. Emerging research explores RNA interference and gene editing approaches to suppress ADAMTS5 expression. Beyond osteoarthritis, ADAMTS5 polymorphisms are associated with intervertebral disc degeneration and cardiovascular remodeling, expanding its therapeutic relevance across multiple disease contexts.