α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes*

By M. Tortorella, E. Arner, Robert L. Hills, A. Easton, J. Korte-Sarfaty, K. Fok, A. Wittwer, Rui-Qin Liu, A. Malfait. 2004

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Osteoarthritis is characterized by the loss of aggrecan and collagen from the cartilage extracellular matrix. The proteinases responsible for the breakdown of cartilage aggrecan include ADAMTS-4 (aggrecanase 1) and ADAMTS-5 (aggrecanase 2). Post-translational inhibition of ADAMTS-4/-5 activity may be important for maintaining normal homeostasis of aggrecan metabolism, and thus, any disruption to this inhibition could lead to accelerated aggrecan breakdown. To date TIMP-3 (tissue inhibitor of matrix metalloproteinases-3) is the only endogenous inhibitor of ADAMTS-4/-5 that has been identified. In the present studies we identify α2-macroglobulin (α2M) as an additional endogenous inhibitor of ADAMTS-4 and ADAMTS-5. α2M inhibited the activity of both ADAMTS-4 and ADAMTS-5 in a concentration-dependent manner, demonstrating 1:1 stoichiometry with second-order rate constants on the order of 106 and 105 m-1 s-1, respectively. Inhibition of the aggrecanases was mediated by proteolysis of the bait region within α2M, resulting in physical entrapment of these proteinases. Both ADAMTS-4 and ADAMTS-5 cleaved α2M at Met690/Gly691, representing a novel proteinase cleavage site within α2M and a novel site of cleavage for ADAMTS-4 and ADAMTS-5. Finally, the use of the anti-neoepitope antibodies to detect aggrecanase-generated α2M-fragments in synovial fluid was investigated and found to be uninformative.

Subfields: Cancer Research, Oncology, Rheumatology