TIMP-3 Is a Potent Inhibitor of Aggrecanase 1 (ADAM-TS4) and Aggrecanase 2 (ADAM-TS5)*

By M. Kashiwagi, M. Tortorella, Hideaki Nagase, K. Brew. 2001

538 citations recorded by the source corpus.

The proteoglycan aggrecan is an important major component of cartilage matrix that gives articular cartilage the ability to withstand compression. Increased breakdown of aggrecan is associated with the development of arthritis and is considered to be catalyzed by aggrecanases, members of the ADAM-TS family of metalloproteinases. Four endogenous tissue inhibitors of metalloproteinases (TIMPs) regulate the activities of functional matrix metalloproteinases (MMPs), enzymes that degrade most components of connective tissue, but no endogenous factors responsible for the regulation of aggrecanases have been found. We show here that the N-terminal inhibitory domain of TIMP-3, a member of the TIMP family that has functional properties distinct from other TIMPs, is a strong inhibitor of human aggrecanases 1 and 2, with K i values in the subnanomolar range. This truncated inhibitor, which lacks the C-terminal domain that is responsible for interactions with molecules other than active metalloproteinases, is produced at high yield by bacterial expression and folding from inclusion bodies. This provides a starting point for developing a biologically available aggrecanase inhibitor suitable for the treatment of arthritis.

Subfields: Cancer Research, Hematology, Molecular Biology

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Citations in the corpus

Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. (2008, background): “The inhibitory properties of TIMP-3 are different from the rest, because it inhibits ADAMs (A Disintigrin And Metalloproteinase) [92].”
How matrix metalloproteinases regulate cell behavior. (2001, background): “TIMP3 is also unique in its ability to inhibit ADAMs-10 and -17, ADAMTS-4, and ADAMTS-5 (Kashiwagi et al. 2001), whereas TIMP1 can inhibit ADAMTS-1 (Tortorella et al. 1999).”
ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. (2002, background): “For example, TIMP1 and TIMP3 had been shown to inhibit ADAMTS4 activity completely at 500 nm [24–26].”
Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. (2018, background): “…metalloproteinase inhibition profile including ADAM-10, ADAM-12, and ADAM-17 as well as a disintegrin and metalloproteinase with thrombospondin motif ADAMTS-1, ADAMTS-2, ADAMTS-4 and ADAMTS-5 (Amour et al., 2000; Kashiwagi et al., 2001; Rodriguez-Manzaneque et al., 2002; Jacobsen et al., 2008).”
Tissue inhibitors of metalloproteinases (2011, background): “TIMP3 has a much broader inhibition profile, including ADAM10 [9], ADAM12 [10], ADAM17 [11] and several ADAMTSs (ADAMTS1, ADAMTS2, ADAMTS4 and ADAMTS5) [12-14].”
Strategies for MMP inhibition in cancer: innovations for the post-trial era (2002, background): “Although MMPIs were first designed to block MMPs, it is now known that these reagents might also cross-inhibit ADAMs and ADAMTS”
The role of TIMPs in regulation of extracellular matrix proteolysis. (2015, background): “The proteolytic activity of ADAM10 can be inhibited by TIMP1 and -3, whereas, TIMP3 alone is an efficient inhibitor of ADAMTS4 and -TS5, which are postulated to cleave aggrecan, a component of cartilage matrix [8–10].”
The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3 (2009, methodology): “N-TIMP-3 can be successfully expressed in E. coli and refolded in vitro (Kashiwagi et al., 2001), but we have not been able to refold full-length TIMP-3 using this system.”
The ADAMs family of metalloproteases: multidomain proteins with multiple functions. (2003, background): “However, the TIMPs are not totally selective for MMPs. TIMP-3 also inhibits ADAM17 (Amour et al. 2000) and ADAM12 (Loechel et al. 2000), as well as ADAM-TS4 and ADAM-TS5 (Kashiwagi et al. 2001).”