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J. Biol. Chem., Vol. 279, Issue 17, 17554-17561, April 23, 2004

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₂-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes^*

Micky D. Tortorella, Elizabeth C. Arner, Robert Hills, Alan Easton, Jennifer Korte-Sarfaty, Kam Fok, Arthur J. Wittwer, Rui-Qin Liu¶, and Anne-Marie Malfait

From the Pfizer Global Research and Development, Chesterfield, Missouri 63017 and ^¶Bristol-Myers Squibb, Wilmington, Delaware 19880-0400

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 ₂-macroglobulin (₂M) as an additional endogenous inhibitor of ADAMTS-4 and ADAMTS-5. ₂M 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 ₂M, resulting in physical entrapment of these proteinases. Both ADAMTS-4 and ADAMTS-5 cleaved ₂M at Met⁶⁹⁰/Gly⁶⁹¹, representing a novel proteinase cleavage site within ₂M and a novel site of cleavage for ADAMTS-4 and ADAMTS-5. Finally, the use of the anti-neoepitope antibodies to detect aggrecanase-generated ₂M-fragments in synovial fluid was investigated and found to be uninformative.

Received for publication, December 1, 2003 , and in revised form, January 6, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Pfizer Global Research and Development, 700 Chesterfield Pkwy., Chesterfield, MO 63017. Tel.: 636-247-7517; Fax: 636-247-6313; E-mail: micky.d.tortorella{at}pfizer.com.

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