ADAMTS-4, also known as aggrecanase-1, was first described as a protein elevated in arthritic synovium. Initial observations indicated a role for ADAMTS-4 in aggrecan cleavage and cartilage destruction, especially in arthritis. Aggrecan, versican and brevican are all cleaved by ADAMTS-4, and specific inhibition of ADAMTS-4 appears to block degradation of these matrix components. Induction of ADAMTS-4 by LPS, IL-1, and retinoic acid suggested the possibility that ADAMTS-4 could be involved in inflammation, and many labs are looking at the role of ADAMTS-4 in arthritis. A member of the metalloproteinase family containing disintegrin-like domains (ADAMs) the function of ADAMTS-4 is still poorly understood. ADAMTS-4 contains the canonical HExxHxxxxxH zinc metalloproteinase motif, and has been shown to be proteolytically active on a range of substrates. ADAMTS-4 is inhibited by the endogenous MMP inhibitors, TIMP-1, 2, 3 and 4 but most efficiently by TIMP-3 (IC50 =7.9 nM). In addition to the metalloprotease domain, ADAMTS-4 has a propeptide domain, a Prohormone Convertase (PC, furin) cleavage site, a cysteine-rich domain and thrombospondin-1 like domains. ADAMTS-4 does not have a transmembrane domain, unlike many of the ADAMs proteases, and is a secreted protein. Other ADAMs family members (ADAM-10, ADAM-17) have been more thoroughly studied, and are known to play key roles in inflammation, growth factor maturation and release, and a wide range of other functions. The full length ADAMTS-4 sequence codes for a 837 amino acid protein, with a predicted mass is 90.244 kD, but glycosylation and the abundance of cysteine residues gives ADAMTS-4 a greater apparent molecular weight on reduced SDS PAGE gels. RP2ADAMTS-4 recognizes the zymogen of ADAMTS-4 at 98 kD in reduced Western blots, activated forms at 64 kD (major bands), and breakdown products at 30 kD of cell lysates. RP2ADAMTS-4 detects a band at about 29 kD in cell culture media, which may be the propeptide domain shed after furin cleavage. A recommended starting concentration for Western blots is 1:1000 when using colorimetric substrates such as BCIP/NBT, and 1:5000 for chemiluminescent substrates. Higher concentrations of antibody may be needed for samples from more distantly related species. EDTA/EGTA treatment of tissues or lysates is required to see latent zymogen.

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