A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) (ADAMTS-4/5)

A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4 and ADAMTS-5) are secreted zinc-dependent enzymes that function as the primary aggrecanases in human articular cartilage (UniProt P59508; UniProt Q9UNA0). They play a critical role in the degradation of aggrecan, the major proteoglycan responsible for the compressive resistance and elasticity of the joint matrix. In pathological conditions such as osteoarthritis (OA), the overactivity of these enzymes leads to the depletion of aggrecan, which precedes collagen degradation and irreversible joint damage (Glasson et al., Nature, 2005). While ADAMTS-4 is often upregulated in human osteoarthritic cartilage, ADAMTS-5 is generally considered the more potent and dominant mediator of cartilage destruction. Therapeutic development has focused on creating selective inhibitors, including small molecules like GLPG1972 and monoclonal antibodies like M6495, to act as disease-modifying osteoarthritis drugs (DMOADs) (ClinicalTrials.gov NCT03595137). However, achieving high selectivity to avoid side effects associated with the inhibition of related metalloproteinases remains a significant challenge in clinical translation.

Other names

Aggrecanase-1Aggrecanase-2ADMP-1ADMP-2

Selective inhibition of the catalytic activity of ADAMTS-4 and ADAMTS-5 to prevent the cleavage of aggrecan at the Glu373-Ala374 bond in the interglobular domain, thereby preserving cartilage structural integrity (UniProt P59508, Q9UNA0).