Tortorella, Curriculum Vitae 2014
MICKY D TORTORELLA
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences
Room A419
190 Kai Yuan Avenue, Science Park
Guangzhou, China 510530
(Cell China) 186-8888-8347
(Email China) m.tortorella@gibh.org
(Cell USA) 636-293-9612
(Email USA) micky.d.tortorella@gmail.com
Background:
The extracellular matrix (ECM) comprises a complex network of many
macromolecules such as proteoglycans, collagens, glycoproteins and
polysaccharides. These matrix proteins play an essential role in the
assembly of cells to form tissues and provide the correct environment for
cell migration, differentiation and growth. ECM remodeling is important in
numerous biological processes including tissue resorption and repair. My
previous work has focused on understanding the biochemical mechanisms
involved in the turnover and degradation of the cartilage ECM, which led to
the discovery, characterization and crystallization of ADAMTS-4 and -5, two
enzymes responsible for aggrecan catabolism in arthritic diseases. Some of
my current research continues to focus on elucidating the mechanisms that
mediate cartilage and bone degradation during the progression of
osteoarthritis (OA) and developing therapies for blocking these processes
using innovative biochemical, biophysical, molecular and cell imaging
technologies.
The illustration depicts an overlay of the crystal structure of the
catalytic domain of ADAMTS-5, a protease responsible for the
breakdown of the matrix molecule aggrecan, bound to an inhibitor
and eroding human, osteoarthritic articular cartilage stained with
hematoxylin and eosin.
Interests:
(1) To lead and provide direction to a discovery
team and apply basic biology to the drug discovery
process, including identification of novel targets,
innovation in assay development and in vivo
models of disease. (2) The role of proteinases in
mediating the breakdown of the extracellular matrix in disease.
Experience:
2009 – Present Guangzhou Institutes of Biomedicine and Health (GIBH),
Guangzhou China
Chief Technology Officer & Vice President of Drug Discovery Research
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Tortorella, Curriculum Vitae 2014
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Establish the overall strategic direction for the Drug Discovery
Pipeline (DDP) at GIBH.
Provide leadership to enable the discovery of new targets and the
development of innovative small molecule therapeutics in response to
unmet medical needs within multiple therapeutic areas.
Insure that a sufficient number of new chemical entities are
successfully promoted to the Development Track each year,
enhancing the pipeline of drugs necessary for GIBH’s sustainable
growth.
Oversee the DDP, which includes: Medicinal Chemistry, Structural
Biology, Screening, PK/PD and Biomarkers.
Coordinated the successful creation of several companies in China
using assets developed at GIBH including GZstem (stem cell based
company) in 2010.
2003 — 2009 Pfizer, St Louis Missouri
Senior Principal Scientist (Inflammatory Diseases)
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Project leader (OA target).
Project champion (2 OA targets).
Coordinated the efforts of multiple team members to establish
objectives, strategies and timelines.
Studied the role of proprotein convertases in the activation of latent
metalloproteinases in articular cartilage.
Developed peptide therapeutics for intra-articular injection for the
treatment of OA.
Studied the dynamic relationship between aggrecan and collagen
breakdown, chondrocyte cloning, chondrocyte apoptosis, osteophyte
formation, subchondral bone sclerosis and pain using KO mice.
Established external strategic alliances to advance project goals.
2001 — 2003 Pharmacia*, Skokie, Illinois. *Acquired by Pfizer in 2003
Senior Principal Scientist (Joint Biology)
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Project leader (OA target).
Coordinated the efforts of multiple team members to establish
objectives, strategies and timelines.
Studied the role of ADAMTS proteins in arthritic diseases.
Identified several novel mediators of cartilage degradation in
osteoarthritis using pathway mapping and proteonomics.
Validated multiple biomarkers of cartilage degradation.
1999 — 2001 Imperial College of London, Kennedy Institute of
Rheumatology, Hammersmith, London.
Research Scientist (Matrix Biology)
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Tortorella, Curriculum Vitae 2014
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Studied the role of cartilage aggrecanase-1 (ADAMTS-4) and
aggrecanase-2 (ADAMTS-5) in in vitro and in vivo models of cartilage
degradation.
Explored the role of fibronectin peptides in mediating cartilage
erosion and the mRNA and protein expression of aggrecanases.
Researched the role of a novel activity “fibronectinases” in the
cleavage of cartilage fibronectin and its importance in cartilage
metabolism
Examined the role of an enzyme involved in the C-terminal truncation
of aggrecan in older adults and the potential link to OA.
Designed multiple-site-binding inhibitors (substrate plus enzyme).
DuPont Pharmaceuticals, Wilmington, Delaware.
1997 — 1999 Research Scientist
1994 — 1997 Staff Scientist
1992 — 1994 Associate Scientist
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Studied the role of MMPs in the breakdown of articular cartilage.
Identified and purified two novel metalloproteinases, aggrecanase-1
(ADAMTS-4) and aggrecanase-2 (ADAMTS-5) in bovine nasal cartilage
implicated in the breakdown of aggrecan in OA.
Characterized the enzyme activity and substrate specificity of
ADAMTS-4 and ADAMTS-5.
Developed and validated several aggrecan neoepitope antibodies as
biomarkers of cartilage breakdown.
Education:
1999 — 2001 Imperial College of London, Kennedy Institute of
Rheumatology, Hammersmith, London. Graduate student in
the biochemistry department.
1985 — 1990 University of Delaware, Newark, Delaware.
Bachelors in Biological Sciences (Biochemistry track), Cum
Laude, GPA 3.5/4.0 Class rank 232/2918; Dean’s list 7/9
semesters.
Laboratory Proficiencies:
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PCR
Cloning
Peptide chemistry
Affinity sensor
Western/Northern
N-terminal sequencing
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- Enzyme assays
- Tissue culture
- Cell labelling
- Protein purification
- HTS screening
- HPLC
- Protein expression
- Mass spectrometry
- Molecular modelling
- ELISA
- Protein binding assays
- Enzymology
Tortorella, Curriculum Vitae 2014
Patents:
o USP 20050090466: Inhibitors of PACE4 for the treatment of arthritis.
o USP 6753176: Aggrecan degrading metallo proteases.
o USP 6521436: Nucleic acids encoding aggrecan degrading metallo
proteases.
o USP 6451575: Aggrecan degrading metallo proteases.
o USP 6326162: Assays and peptide substrate for determining aggrecan
degrading metallo protease activity.
o USP Application 60/145527: Thrombospondin Peptides that Inhibit
Aggrecanase Activity.
o WO 03/005956: A Hydroxamic Acid Thrombospondin Peptide Analog
that Inhibits Aggrecanase Activity.
o USP 6635430: Filtrate plate device and reversible-well plate device.
o USP 2005037432A: Novel biomarkers of aggrecanase activity.
External Collaborations & Strategic Alliances
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Professor Anne-Marie Malfait, PhD, MD at Rush Medical Center
(www.rush.edu). Understanding the biochemistry of OA pain using
transgenic mice.
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The Center for World Health & Medicine at Saint Louis University
(www.cwhm.org). Development of inhibitors of plasmepsin V as novel
anti-malarial agents.
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John J. Talley, PhD and Mark Obukowicz, PhD. Development of 3rd
generation Cox-2 selective inhibitors for the treatment of
inflammation-mediated cancers.
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Professor Jufang He, PhD at Hong Kong Polytechnic University
(http://www.polyu.edu.hk). Advancement of CCKBR agonists for the
improvement of memory.
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Dr. Jinsong Zhu, CEO of Plexera Inc. (www.plexera.com).
Development of compound micro-array chips for rapid repositioning
of clinical candidate compounds.
Publications:
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Tortorella, Curriculum Vitae 2014
1. Yanmei Zhang, Wei-Xing Dan, Jianqi Liu, Micky D. Tortorella,
Zhengchao Tu and John J Talley
Palladium-catalyzed synthesis of trimethylsilyl substituted
benzopyran derivatives
(2013) The Open Organic Chemistry Journal 7, pp.15-20.
2. Miller RE, Lu Y, Tortorella MD, Malfait AM.
Genetically engineered mouse models reveal the importance of
proteases as osteoarthritis drug targets
(2013) Curr Rheumatol Rep.15(8):350.
3. Morgen, M., Tung, D., Boras, B., Miller, W., Malfait, A.-M.,
Tortorella, M.
Nanoparticles for improved local retention after intra-articular
injection into the knee joint
(2013) Pharmaceutical Research, 30 (1), pp. 257-268. Cited 1 time.
4. Malfait, A.-M., Seymour, A.B., Gao, F., Tortorella, M.D., Le
Graverand-Gastineau, M.-P.H., Wood, L.S., Doherty, M., Doherty, S.,
Zhang, W., Arden, N.K., Vaughn, F.L., Leaverton, P.E., Spector, T.D.,
Hart, D.J., Maciewicz, R.A., Muir, K.R., Das, R., Sorge, R.E.,
Sotocinal, S.G., Schorscher-Petcu, A., Valdes, A.M., Mogil, J.S.
A role for PACE4 in osteoarthritis pain: Evidence from human genetic
association and null mutant phenotype
(2012) Annals of the Rheumatic Diseases, 71 (6), pp. 1042-1048. Cited
4 times.
5. Li, J., Anemaet, W., Diaz, M.A., Buchanan, S., Tortorella, M.,
Malfait, A.M., Mikecz, K., Sandy, J.D., Plaas, A.
Knockout of ADAMTS5 does not eliminate cartilage aggrecanase
activity but abrogates joint fibrosis and promotes cartilage aggrecan
deposition in murine osteoarthritis models
(2011) Journal of Orthopaedic Research, 29 (4), pp. 516-522. Cited 14
times.
6. Zhang, S., Chen, S., Li, W., Guo, X., Zhao, P., Xu, J., Chen, Y., Pan,
Q., Liu, X., Zychlinski, D., Lu, H., Tortorella, M.D., Schambach, A.,
Wang, Y., Pei, D., Esteban, M.A.
Rescue of ATP7B function in hepatocyte-like cells from Wilson's
disease induced pluripotent stem cells using gene therapy or the
chaperone drug curcumin
(2011) Human Molecular Genetics, 20 (16), art. no. ddr223, pp. 31763187. Cited 19 times.
7. Shieh, H.-S., Tomasselli, A.G., Mathis, K.J., Schnute, M.E., Woodard,
S.S., Caspers, N., Williams, J.M., Kiefer, J.R., Munie, G., Wittwer, A.,
Malfait, A.-M., Tortorella, M.D.
Structure analysis reveals the flexibility of the ADAMTS-5 active site
(2011) Protein Science, 20 (4), pp. 735-744. Cited 4 times.
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6. Dufield, D.R., Nemirovskiy, O.V., Jennings, M.G., Tortorella, M.D.,
Malfait, A.M., Mathews, W.R.
An immunoaffinity liquid chromatography-tandem mass spectrometry
assay for detection of endogenous aggrecan fragments in biological
fluids: Use as a biomarker for aggrecanase activity and cartilage
degradation
(2010) Analytical Biochemistry, 406 (2), pp. 113-123. Cited 12 times.
7. Byun, S., Tortorella, M.D., Malfait, A.-M., Fok, K., Frank, E.H.,
Grodzinsky, A.J.
Transport and equilibrium uptake of a peptide inhibitor of PACE4 into
articular cartilage is dominated by electrostatic interactions
(2010) Archives of Biochemistry and Biophysics, 499 (1-2), pp. 3239. Cited 5 times.
8. Malfait, A.M., Ritchie, J., Gil, A.S., Austin, J.-S., Hartke, J., Qin, W.,
Tortorella, M.D., Mogil, J.S.
ADAMTS-5 deficient mice do not develop mechanical allodynia
associated with osteoarthritis following medial meniscal
destabilization
(2010) Osteoarthritis and Cartilage, 18 (4), pp. 572-580. Cited 19
times.
9. Zack, M.D., Melton, M.A., Stock, J.L., Storer, C.E., Barve, R.A.,
Minnerly, J.C., Weiss, D.J., Stejskal, J.A., Tortorella, M.D., Turk,
J.R., Shevlin, K.M., Malfait, A.-M.
Reduced incidence and severity of experimental autoimmune arthritis
in mice expressing catalytically inactive A disintegrin and
metalloproteinase 8 (ADAM8)
(2009) Clinical and Experimental Immunology, 158 (2), pp. 246256. Cited 7 times.
10. Tortorella, M.D., Tomasselli, A.G., Mathis, K.J., Schnute, M.E.,
Woodard, S.S., Munie, G., Williams, J.M., Caspers, N., Wittwer, A.J.,
Malfait, A.-M., Shieh, H.-S.
Structural and inhibition analysis reveals the mechanism of selectivity
of a series of aggrecanase inhibitors
(2009) Journal of Biological Chemistry, 284 (36), pp. 2418524191. Cited 20 times.
11. Zack, M.D., Malfait, A.-M., Skepner, A.P., Yates, M.P., Griggs, D.W.,
Hall, T., Hills, R.L., Alston, J.T., Nemirovskiy, O.V., Radabaugh,
M.R., Leone, J.W., Arner, E.C., Tortorella, M.D.
ADAM-8 isolated from human osteoarthritic chondrocytes cleaves
fibronectin at Ala271
(2009) Arthritis and Rheumatism, 60 (9), pp. 2704-2713. Cited 8
times.
12. Tortorella, M.D., Malfait, F., Barve, R.A., Shieh, H.-S., Malfait, A.-M.
A review of the ADAMTS family, pharmaceutical targets of the future
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(2009) Current Pharmaceutical Design, 15 (20), pp. 2359-2374. Cited
18 times.
13. Malfait, A.M., Tortorella, M., Thompson, J., Hills, R., Meyer, D.M.,
Jaffee, B.D., Chinn, K., Ghoreishi-Haack, N., Markosyan, S., Arner,
E.C.
Intra-articular injection of tumor necrosis factor-α in the rat: an
acute and reversible in vivo model of cartilage proteoglycan
degradation
(2009) Osteoarthritis and Cartilage, 17 (5), pp. 627-635. Cited 5
times.
14. Malfait, A.-M., Arner, E.C., Song, R.-H., Alston, J.T., Markosyan, S.,
Staten, N., Yang, Z., Griggs, D.W., Tortorella, M.D.
Proprotein convertase activation of aggrecanases in cartilage in situ
(2008) Archives of Biochemistry and Biophysics, 478 (1), pp. 4351. Cited 30 times.
15. Tortorella, M.D., Malfait, A.M.
Will the real aggrecanase(s) step up: Evaluating the criteria that
define aggrecanase activity in osteoarthritis
(2008) Current Pharmaceutical Biotechnology, 9 (1), pp. 16-23. Cited
18 times.
16. Shieh, H.-S., Mathis, K.J., Williams, J.M., Hills, R.L., Wiese, J.F.,
Benson, T.E., Kiefer, J.R., Marino, M.H., Carroll, J.N., Leone, J.W.,
Malfait, A.-M., Arner, E.C., Tortorella, M.D., Tomasselli, A.
High resolution crystal structure of the catalytic domain of ADAMTS-5
(aggrecanase-2)
(2008) Journal of Biological Chemistry, 283 (3), pp. 1501-1507. Cited
33 times.
17. Blair, W.S., Cao, J., Jackson, L., Jimenez, J., Peng, Q., Wu, H.,
Isaacson, J., Butler, S.L., Chu, A., Graham, J., Malfait, A.-M.,
Tortorella, M., Patick, A.K.
Identification and characterization of UK-201844, a novel inhibitor
that interferes with human immunodeficiency virus type 1 gp160
processing
(2007) Antimicrobial Agents and Chemotherapy, 51 (10), pp. 35543561. Cited 9 times.
18. Wittwer, A.J., Hills, R.L., Keith, R.H., Munie, G.E., Arner, E.C.,
Anglin, C.P., Malfait, A.-M., Tortorella, M.D.
Substrate-dependent inhibition kinetics of an active site-directed
inhibitor of ADAMTS-4 (aggrecanase 1)
(2007) Biochemistry, 46 (21), pp. 6393-6401. Cited 16 times.
19. Hall, T., Fok, K.F., Liu, M.M., Zobel, J.F., Marino, M.H., Malfait, A.M., Tortorella, M.D., Tomasselli, A.G.
A high performance liquid chromatography assay for monitoring
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Tortorella, Curriculum Vitae 2014
proprotein convertase activity
(2007) Journal of Chromatography A, 1148 (1), pp. 46-54. Cited 3
times.
20. Hills, R., Mazzarella, R., Fok, K., Liu, M., Nemirovskiy, O., Leone, J.,
Zack, M.D., Arner, E.C., Viswanathan, M., Abujoub, A.,
Muruganandam, A., Sexton, D.J., Bassill, G.J., Sato, A.K., Malfait, A.M., Tortorella, M.D.
Identification of an ADAMTS-4 cleavage motif using phage display
leads to the development of fluorogenic peptide substrates and
reveals matrilin-3 as a novel substrate
(2007) Journal of Biological Chemistry, 282 (15), pp. 1110111109. Cited 19 times.
21. Song, R.-H., Tortorella, M.D., Malfait, A.-M., Alston, J.T., Yang, Z.,
Arner, E.C., Griggs, D.W.
Aggrecan degradation in human articular cartilage explants is
mediated by both ADAMTS-4 and ADAMTS-5
(2007) Arthritis and Rheumatism, 56 (2), pp. 575-585. Cited 114
times.
22. Zack, M.D., Arner, E.C., Anglin, C.P., Alston, J.T., Malfait, A.-M.,
Tortorella, M.D.
Identification of fibronectin neoepitopes present in human
osteoarthritic cartilage
(2006) Arthritis and Rheumatism, 54 (9), pp. 2912-2922. Cited 14
times.
23. Tortorella, M.D., Arner, E.C., Hills, R., Gormley, J., Fok, K., Pegg,
L., Munie, G., Malfait, A.-M.
ADAMTS-4 (aggrecanase-1): N-Terminal activation mechanisms
(2005) Archives of Biochemistry and Biophysics, 444 (1), pp. 3444. Cited 43 times.
24. Tortorella, M.D., Arner, E.C., Hills, R., Easton, A., Korte-Sarfaty, J.,
Fok, K., Wittwer, A.J., Liu, R.-Q., Malfait, A.-M.
α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5
and Represents an Endogenous Inhibitor of These Enzymes
(2004) Journal of Biological Chemistry, 279 (17), pp. 1755417561. Cited 52 times.
25. Wang, P., Tortorella, M., England, K., Malfait, A.-M., Thomas, G.,
Arner, E.C., Pei, D.
Proprotein Convertase Furin Interacts with and Cleaves Pro-ADAMTS4
(Aggrecanase-1) in the trans-Golgi Network
(2004) Journal of Biological Chemistry, 279 (15), pp. 1543415440. Cited 67 times.
26. Tortorella, M.D., Malfait, A.-M.
The Usual Suspects: Verdict Not Guilty?
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(2003) Arthritis and Rheumatism, 48 (12), pp. 3304-3307. Cited 10
times.
27. Pratta, M.A., Yao, W., Decicco, C., Tortorella, M.D., Liu, R.-Q.,
Copeland, R.A., Magolda, R., Newton, R.C., Trzaskos, J.M., Arner,
E.C.
Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage
(2003) Journal of Biological Chemistry, 278 (46), pp. 4553945545. Cited 105 times.
28. Cherney, R.J., Mo, R., Meyer, D.T., Wang, L., Yao, W., Wasserman,
Z.R., Liu, R.-Q., Covington, M.B., Tortorella, M.D., Arner, E.C., Qian,
M., Christ, D.D., Trzaskos, J.M., Newton, R.C., Magolda, R.L.,
Decicco, C.P.
Potent and selective aggrecanase inhibitors containing cyclic P1
substituents
(2003) Bioorganic and Medicinal Chemistry Letters, 13 (7), pp. 12971300. Cited 30 times.
29. Tortorella, M.D., Liu, R.-Q., Burn, T., Newton, R.C., Arner, E.
Characterization of human aggrecanase 2 (ADAM-TS5): Substrate
specificity studies and comparison with aggrecanase 1 (ADAM-TS4)
(2002) Matrix Biology, 21 (6), pp. 499-511. Cited 91 times.
30. Malfait, A.-M., Liu, R.-Q., Ijiri, K., Komiya, S., Tortorella, M.D.
Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation
in osteoarthritic cartilage
(2002) Journal of Biological Chemistry, 277 (25), pp. 2220122208. Cited 160 times.
31. Osman, M., Tortorella, M., Londei, M., Quaratino, S.
Expression of matrix metalloproteinases and tissue inhibitors of
metalloproteinases define the migratory characteristics of human
monocyte-derived dendritic cells
(2002) Immunology, 105 (1), pp. 73-82. Cited 44 times.
32. Yamanishi, Y., Boyle, D.L., Clark, M., Maki, R.A., Tortorella, M.D.,
Arner, E.C., Firestein, G.S.
Expression and regulation of aggrecanase in arthritis: The role of
TGF-β
(2002) Journal of Immunology, 168 (3), pp. 1405-1412. Cited 93
times.
33. Yao, W., Wasserman, Z.R., Chao, M., Reddy, G., Shi, E., Liu, R.-Q.,
Covington, M.B., Arner, E.C., Pratta, M.A., Tortorella, M., Magolda,
R.L., Newton, R., Qian, M., Ribadeneira, M.D., Christ, D., Wexler,
R.R., Decicco, C.P.
Design and synthesis of a series of (2R)-N4-hydroxy-2-(3hydroxybenzyl)-N1- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1yl]butanediamide derivatives as potent, selective, and orally
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Tortorella, Curriculum Vitae 2014
bioavailable aggrecanase inhibitors
(2001) Journal of Medicinal Chemistry, 44 (21), pp. 3347-3350. Cited
47 times.
34. Tortorella, M.D., Malfait, A.-M., Deccico, C., Arner, E.
The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2)
in a model of cartilage degradation
(2001) Osteoarthritis and Cartilage, 9 (6), pp. 539-552. Cited 163
times.
35. Kashiwagi, M., Tortorella, M., Nagase, H., Brew, K.
TIMP-3 Is a Potent Inhibitor of Aggrecanase 1 (ADAM-TS4) and
Aggrecanase 2 (ADAM-TS5)
(2001) Journal of Biological Chemistry, 276 (16), pp. 1250112504. Cited 282 times.
36. Pratta, M.A., Tortorella, M.D., Arner, E.C.
Age-related changes in aggrecan glycosylation affect cleavage by
aggrecanase
(2000) Journal of Biological Chemistry, 275 (50), pp. 3909639102. Cited 55 times.
37. Tortorella, M., Pratta, M., Liu, R.-Q., Abbaszade, I., Ross, H., Burn,
T., Arner, E.
The thrombospondin motif of Aggrecanase-1 (ADAMTS-4) is critical for
aggrecan substrate recognition and cleavage
(2000) Journal of Biological Chemistry, 275 (33), pp. 2579125797. Cited 127 times.
38. Tortorella, M.D., Pratta, M., Liu, R.-Q., Austin, J., Ross, O.H.,
Abbaszade, I., Burn, T., Arner, E.
Sites of aggrecan cleavage by recombinant human aggrecanase-1
(ADAMTS-4)
(2000) Journal of Biological Chemistry, 275 (24), pp. 1856618573. Cited 154 times.
39. Abbaszade, I., Liu, R.-Q., Yang, F., Rosenfeld, S.A., Ross, O.H., Link,
J.R., Ellis, D.M., Tortorella, M.D., Pratta, M.A., Hollist, J.M., Wynn,
R., Duke, J.L., George, H.J., Hillman Jr., M.C., Murphy, K., Wiswall,
B.H., Copeland, R.A., Decicco, C.P., Bruckner, R., Nagase, H., Itoh,
Y., Newton, R.C., Magolda, R.L., Trzaskos, J.M., Hollis, G.F., Arner,
E.C., Burn, T.C.
Cloning and characterization of ADAMTS11, an aggrecanase from the
ADAMTS family
(1999) Journal of Biological Chemistry, 274 (33), pp. 2344323450. Cited 340 times.
40. Arner, E.C., Pratta, M.A., Decicco, C.P., Xue, C.-B., Newton, R.C.,
Trzaskos, J.M., Magolda, R.L., Tortorella, M.D.
Aggrecanase. A target for the design of inhibitors of cartilage
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Tortorella, Curriculum Vitae 2014
degradation
(1999) Annals of the New York Academy of Sciences, 878, pp. 92107. Cited 41 times.
41. Tortorella, M.D., Burn, T.C., Pratta, M.A., Abbaszade, I., Hollis,
J.M., Liu, R., Rosenfeld, S.A., Copeland, R.A., Decicco, C.P., Wynn,
R., Rockwell, A., Yang, F., Duke, J.L., Solomon, K., George, H.,
Bruckner, R., Nagase, H., Itoh, Y., Ellis, D.M., Ross, H., Wiswall,
B.H., Murphy, K., Hillman Jr., M.C., Hollis, G.F., Newton, R.C.,
Magolda, R.L., Trzaskos, J.M., Arner, E.C.
Purification and cloning of aggrecanase-1: A member of the ADAMTS
family of proteins
(1999) Science, 284 (5420), pp. 1664-1666. Cited 472 times.
42. Arner, E.C., Pratta, M.A., Trzaskos, J.M., Decicco, C.P., Tortorella,
M.D.
Generation and characterization of aggrecanase. A soluble, cartilagederived aggrecan-degrading activity
(1999) Journal of Biological Chemistry, 274 (10), pp. 65946601. Cited 106 times.
43. Arner, E.C., Hughes, C.E., Decicco, C.P., Caterson, B., Tortorella,
M.D.
Cytokine-induced cartilage proteoglycan degradation is mediated by
aggrecanase
(1998) Osteoarthritis and Cartilage, 6 (3), pp. 214-228. Cited 106
times.
44. Tortorella, M.D., Pratta, M.A., Fox, J.W., Arner, E.C.
The interglobular domain of cartilage aggrecan is cleaved by
hemorrhagic metalloproteinase HT-d (Atrolysin C) at the matrix
metalloproteinase and aggrecanase sites
(1998) Journal of Biological Chemistry, 273 (10), pp. 58465850. Cited 27 times.
45. Trzaskos, J.M., Scherele, P.A., Manos, E.J., Feezer, W.S., Tortorella,
M.D., Arner, E.C., Favata, M.F.
Inhibition of mapkk (MEK) prevents upregulation of
metalloproteinases in fibroblasts
(1997) FASEB Journal, 11 (9).
46. Tortorella, M.D., Arner, E.C.
A fluorescent enzyme-linked immunosorbent assay (FELISA) for
stromelysin using a polyclonal antisera to human stromelysin with
broad species cross-reactivity
(1997) Inflammation Research, 46 (SUPPL. 2), pp. S120-S121. Cited 4
times.
47. Tortorella, M.D., Arner, E.C.
A high-throughput assay for stromelysin using a casein-resorufin
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substrate
(1997) Inflammation Research, 46 (SUPPL. 2), pp. S122-S123. Cited 7
times.
48. Arner, E.C., Decicco, C.P., Cherney, R., Tortorella, M.D.
Cleavage of native cartilage aggrecan by neutrophil collagenase
(MMP-8) is distinct from endogenous cleavage by aggrecanase
(1997) Journal of Biological Chemistry, 272 (14), pp. 92949299. Cited 37 times.
49. Arner, E.C., DiMeo, T.M., Pratta, M.A., Tortorella, M.D.
Interleukin-1 induces aggrecanase-mediated cleavage in human
articular cartilage without up-regulating stromelysin or
glycosaminoglycan release
(1995) Acta Orthopaedica Scandinavica,
Supplement, 66 (266), pp. 153-154. Cited 1 time.
50. Arner, E.C., Tortorella, M.D.
Signal transduction through chondrocyte integrin receptors induces
matrix metalloproteinase synthesis and synergizes with interleukin-1
(1995) Arthritis and Rheumatism, 38 (9), pp. 1304-1314. Cited 83
times.
Reviews and Book Chapters:
1. Tortorella M.D., Malfait F., Barve R.A., Shieh H.S., and Malfait A.M.
(2009) A Review of the ADAMTS Family, Pharmaceutical Targets of the
Future. Curr Pharm Des. 15(20):2359-74 Review.
2. Tortorella M.D. and Malfait A.M. (2008) Will the real aggrecanase(s)
step up: evaluating the criteria that define aggrecanase activity in
osteoarthritis. Curr Pharm Biotechnol. 9(1):16-23 Review.
3. Malfait A.M., Tortorella M.D., and Arner E.C. (2005) The ADAM
Family of Proteases: ADAMTS-4 and ADAMTS-5. Series: Proteases in
Biology and Disease, Vol. 4. Springer. Book Chapter 14.
4. Tortorella M.D. and Malfait A.M. (2003) The usual suspects: verdict
not guilty? Arthritis & Rheum. 48:3304-7 Editorial.
Abstracts/External Presentations:
1. Arner E.C. and M.Tortorella. Signal transduction through chondrocyte
integrin receptors up-regulates matrix metalloproteinase synthesis and
synergizes with interleukin-1. Orthopaedic Research Society Meeting,
February 1994. (podium)
2. Arner E.C., T.M. DiMeo and M.D. Tortorella. Intra-articular injection of
RGD peptides and fibronectin fragments induce cartilage degradation in
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the rabbit.
Gordon Research Conference on Bioengineering and
Orthopedic Science, August, 1994.
3. Arner E.C. and M.Tortorella.
Integrin signalling induces articular
chondrocyte matrix metalloproteinase synthesis. Philadelphia Immunology
Conference. November, 1994.
4. Arner E.C., T.M. DiMeo and M.Tortorella. RGD peptides and fibronectin
fragments induce cartilage proteoglycan degradation and stromelysin
synthesis in vivo. Second International Congress of the Osteoarthritis
Research Society. December, 1994. (podium)
5. Tortorella, M.D., J.M. Trzaskos, R.L. Magolda, and E.C. Arner Elution of
active stromelysin from cartilage stimulated with interleukin-1.
Orthopaedic Research Society Meeting. February, 1995.
6. C.E. Hughes H. Wang, B. Caterson, M.D. Tortorella, and E.C. Arner.
Timecourse of IL1-induced "aggrecanase" cartilage catabolism indicates
the presence of both different rates of release and different pools of
aggrecan metabolites. Orthopaedic Research Society Meeting. February,
1995.
7. E.C. Arner, T.M. DiMeo, M.A. Pratta, and M.D. Tortorella. Interleukin-1
induces aggrecanase-mediated cleavage in human articular cartilage
without up-regulating stromelysin or glycosaminoglycan release. Eric K.
Fernstrom Symposium on Molecular Markers for Joint and Skeletal
Diseases. May, 1995.
8. E.C. Arner, P. Gunyuzulu, G. Davis, M. Hillman, Jr., H. Ross, M.D.
Tortorella Cleavage of native cartilage aggrecan by neutrophil collagenase
(MMP-8). Matrix Metalloproteinase Gordon Research Conference, July,
1995.
9. C.E. Hughes, B. Caterson, M.D. Tortorella, and E.C. Arner Catabolic
neoepitopes as markers of proteoglycan degradation in arthritis. Matrix
Metalloproteinase Gordon Research Conference. July, 1995
10. M.A. Pratta, M.D. Tortorella, P. Gunyuzulu, G.L Davis, H. George and
E.C. Arner
Co-induction of MMP-3 and MMP-8 synthesis in human
chondrocytes in response to interleukin-1. Trans 42nd Ann Meeting Orthop
Res Soc 21(1): 170, 1996. (podium)
11. M.A. Pratta, T.M. DiMeo, M.D. Tortorella and E.C. Arner.
Effect of
dexamethasone on interleukin-1 induction of stromelysin-1 synthesis in
cartilage and isolated chondrocytes. Trans 42nd Ann Meeting Orthop Res
Soc 21(2): 319, 1996.
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12. E.C. Arner, T.M. DiMeo, M.A. Pratta, and M.D. Tortorella. Interleukin-1
induces aggrecanase-mediated cleavage in human articular cartilage.
Trans 42nd Ann Meeting Orthop Res Soc 21(2): 364, 1996.
13. M.D. Tortorella, C.E. Hughes, H. Wang, B. Caterson, C.P. Decicco and E.C.
Arner Matrix metalloproteinase inhibitors block aggrecanase-mediated
cleavage of cartilage proteoglycan. Trans 42nd Ann Meeting Orthop Res
Soc 21(1): 148, 1996. (podium)
14. E.C. Arner, P. Gunyuzulu, G. Davis, M. Hillman, Jr., H. Ross, M.D.
Tortorella Neutrophil collagenase cleaves purified aggrecan and native
cartilage aggrecan in situ at the aggrecanase site. Trans 42nd Ann Meeting
Orthop Res Soc 21(1): 146, 1996. (podium)
15. E.C. Arner, T.M. DiMeo and M.D. Tortorella. RGD peptides and fibronectin
fragments induce cartilage degradation in the rabbit. Eighth International
Conference of the Inflammation Research Association, October 27-31,
1996. (podium)
16. E.C. Arner, C.P. Decicco, R.A. Copeland, J.V. Giannaras, C.S. Carlson, R.L.
Magolda, M.D. Tortorella.
"Aggrecanase" activity in cartilage from
different species. Eighth International Conference of the Inflammation
Research Association, October 27-31, 1996.
17. E.C. Arner, C.P. Decicco, R.A. Copeland, J.V. Giannaras, M.D. Tortorella.
"Aggrecanase" mediates interleukin-1-induced cartilage degradation.
Eighth International Conference of the Inflammation Research Association,
October 27-31, 1996.
18. T.M. DiMeo, T. Taylor, M.D. Tortorella, B.D. Jaffee and E.C. Arner. Knee
joint involvement in rat adjuvant arthritis: a source of connective tissue
for evaluation of disease pathology. Eighth International Conference of
the Inflammation Research Association, October 27-31, 1996.
19. M.D. Tortorella, E.C. Arner. A fluorescent enzyme-linked immunosorbent
assay (FELISA) for MMP-3 using a polyclonal antisera to human MMP-3 with
broad species cross reactivity. Eighth International Conference of the
Inflammation Research Association, October 27-31, 1996.
20. M.D. Tortorella, J.M. Trzaskos, E.C. Arner. A high-throughput assay for
stromelysin using a casein-resorufin substrate.
Eighth International
Conference of the Inflammation Research Association, October 27-31,
1996.
21. M.D. Tortorella, M.A. Prata, L.M. Bauerle, C.P. Decicco, E.C. Arner.
Matrix metalloproteinase inhibitors, but not NASAIDs, steroids or
tetracyclines, inhibit "aggrecanase"-mediated cartilage degradation.
Eighth International Conference of the Inflammation Research Association,
October 27-31, 1996.
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22. E.C. Arner, C.P. Decicco, M.A. Pratta, R.C. Newton, J.M. Trzaskos, R.L
Magolda, M.D. Tortorella. “Aggrecanase”, and not MMP-1, -2, -3, -8 or –9,
is critical for IL-1-induced cartilage aggrecan degradation. Trans. Orthop.
Res. Soc. 22:454, 1997.
23. M.D. Tortorella, J.M. Trzaskos, E.C. Arner.
Identification and
characterization of an assay which defines the cartilage degrading
enzyme, “aggrecanase”. Trans. Orthop. Res. Soc. 22:452, 1997.
24. E.C. Arner, C.P. Decicco, M.A. Copeland, J.M. Trzaskos, R.L. Magolda,
M.D. Tortorella. Characterization of soluble bovine cartilage
“aggrecanase”. Trans. Orthop. Res. Soc. 22:103, 1997. (podium)
25. M.D. Tortorella, E.C. Arner.
Fibronectin fragments induce matrix
metalloproteinases production and aggrecanase-mediated cartilage
degradation. Trans. Orthop. Res. Soc. 22:106, 1997. (podium)
26. J.M. Trzaskos, P.A. Scherle, E.J. Manos, W.S. Feeser, M.D. Tortorella,
E.C. Arner, M.F. Favata. Inhibition of MEK prevents upregulation of
metalloproteinases in fibroblasts. ASBMB, August, 1997.
27. E.C. Arner, M.A. Pratta, R.C. Newton, J.M. Trzaskos, R.L. Magolda, M.D.
Tortorella.
Comparison of cleavage efficiency of aggrecanase and
stromelysin for the aggrecan core protein. Trans 43nd Ann Meeting Orthop
Res Soc 1998
28. M.A. Pratta, M.D. Tortorella, R.C. Newton, J.M. Trzaskos, R. Magolda, C.
P. DeCicco, B. Schumaker, K.E. Kuettner, A.A. Cole and E.C. Arner.
Interleukin-1 stimulation of bovine nasal cartilage results exclusively in
upregulation of aggrecanase-mediated cleavage. Trans 43nd Ann Meeting
Orthop Res Soc 1998 (podium)
29. Tortorella M.D., M.A. Pratta, J.W. Fox, E.C. Arner. The interglobular
domain of cartilage aggrecan is cleaved by hemorrhagic metalloproteinase
HT-d (atrolysin C) at the matrix metalloproteinase and aggrecanase sites
Trans 43nd Ann Meeting Orthop Res Soc 1998 (podium)
30. Arner E.C., M.D. Tortorella, M.A. Pratta, B.D. Jaffee, R.A. Copeland, C-B.
Xue, R.C. Newton, J.M. Trzaskos, R.L. Magolda, C.P. Decicco.
Aggrecanase: a target for the design of inhibitors of cartilage degradation.
New York Academy of Sciences Conference on Inhibition of Matrix
Metalloproteinases: Therapeutic Applications.
October 21-24, 1998.
(podium)
31. E.C. Arner, T. Burn, M.A. Pratta, R. Liu, J.M. Trzaskos, R.C. Newton, C.P.
Decicco, A.Rockwell, R. Copeland, F. Yang, R. Bruchner, H. George, R.L.
Magolda, M.D. Tortorella. Isolation and identification of “aggrecanase”: a
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novel cartilage aggrecan-degrading metallo- proteinase (ADMP) 45th Ann
Meeting Orthop Res Soc 1999 (podium).
32. M.A. Pratta, M.D. Tortorella, E.C. Arner. Aggrecan glycosylation affects
cleavage by aggrecanase. 45th Ann Meeting Orthop Res Soc 1999.
33. M.D. Tortorella, T. Burn, H. George, R. Liu, L. Abbaszade, J.M. Hollis,
S.A. Rosenfeld, D.M. Ellis, H. Ross, B.H. Wiswall, K. Murphy, R. Wynn, J.L.
Duke, M.C. Hillman, Jr., G.F. Hollis, R.L. Magolda, A. Cole, K. Kuettner,
M.A. Pratta, E.C. Arner. Sites of cleavage of aggrecan by the recombinant
human aggrecan-degrading-metallo-protease (ADMP), “aggrecanase”. 45th
Ann Meeting Orthop Res Soc 1999 (podium).
34. E.C. Arner, T. Burn, M.A. Pratta, R. Liu, J.M. Trzaskos, R.C. Newton, C.P.
Decicco, A. Rockwell, R. Copeland, F. Yang, R. Bruchner, H. George, R.L.
Magolda, M.D. Tortorella. Isolation, purification, cloning and expression
of aggrecanase. Keystone Symposium on Metalloproteases: Chemistry,
Biology and Medicine. February 25-March 3, 1999 (podium).
35. M.D. Tortorella, E.C. Arner, T. Burn and H.Nagase. Purification, cloning
and characterization of aggrecanase-1 and aggrecanase-2: two novel
members of the ADAMTS family. Proteases and their Inhibitors, Tiers, Italy.
Feb 29-30, 2000 (podium).
36. Micky Tortorella, Anne-Marie Malfait and Hideaki Nagase. The role of
ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in cartilage
degradation. Cold Spring Harbor Meeting: Proteolysis and Biological
Control. May 2-6, 2001 (podium).
37. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Inhibition of
ADAM-TS4 (Aggrecanase-1) and ADAM-TS5 (Aggrecanase-2) prevents
aggrecan degradation in osteoarthritic cartilage. Japanese Cartilage
Metabolism Society (JCMS). Maebashi, Japan. March 8-9, 2002 (keynote
speaker).
38. Anne-Marie Malfait, Elizabeth Arner and Micky Tortorella.
2Macroglobulin is Cleaved at a Novel site by ADAMTS-4 and ADAMTS-5 and
Represents an Endogenous Inhibitorof These Enzymes. Trans 49th Ann
Meeting Orthop Res Soc 2003 (podium)
39. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Fibronectin
fragments, but not IL-1 and TNFa, induce aggrecanase- mediated
catabolism of aggrecan in human articular cartilage. Trans 49th Ann
Meeting Orthop Res Soc 2003 (poster).
40. Malfait, A M; Arner, E C; Hills, R; Korte-Sarfaty, J; Fok, K; Pegg, L; Munie,
G; Tortorella, M D. N-Terminal activation of ADAMTS-4 (Aggrecanase-1).
Trans 51st Ann Meeting Orthop Res Soc 2005 (poster).
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41. Micky Tortorella and Anne-Marie Malfait. PACE4 Drives Osteoarthritis
Through Activation of ADAMTS-4 And ADAMTS-5 In The Extracellular Matrix
of Articular Cartilage. The 2005 MMP Gordon Research Conference (Oral).
42. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Isolation from
the Extracellaulr Matrix of OA, A Proprotein Convertase That Activates
Both Latent ADAMTS-4 and ADAMTS-5. Trans 52st Ann Meeting Orthop Res
Soc 2006, Chicago, IL (Oral).
43. Micky Tortorella. ADAMTS4 and 5 in arthritis and cancer. Key note
speaker. IUPHAR 2006 - 15th World Congress of Pharmacology (Part II),
Metalloproteinases as Therapeutical Targets for Cancer Therapy, Beijing,
China, 2-7 July 2006
44. Micky Tortorella. PACE4 Drives Osteoarthritis through Activation of
ADAMTS-4 and ADAMTS-5 in the Extracellular Matrix of Cartilage. Key note
speaker. Gordon Research Conference: Proprotein Processing, Trafficking
& Secretion. July 9-14, 2006 Colby-Sawyer College New London, N H.
45. Micky Tortorella. High Resolution Crystal Structure of the Catalytic
Domain of ADAMTS-5 (Aggrecanase-2). Poster Presentation. Segal North
American Osteoarthritis Workshop. September 7-9, 2007, Chicago, Illinois.
46. Micky Tortorella. Crystal Structure of the Catalytic Domain of ADAMTS-5
(Aggrecanase-2). Podium Presentation. Midwest Connective Tissue
Workshop. December 14-15, 2007, Chicago, Illinois.
47. Micky Tortorella. Key note speaker. Crystal Structure of the Catalytic
Domain of ADAMTS-5 (Aggrecanase-2). 1st Annual Protein and Peptide
Conference (PepCon). April 22-24, 2008, Shenzhen, China.
48. Micky Tortorella, Ingar Lau, Anne-Marie Malfait, Joe Leone, Cindy
Deppeler, Marc Zack, Bill Hood, Elizabeth Arner, Robert L. Hills.
Expression and Characterization of the Disintegrin and Thrombospondin
Domain of ADAMTS-4: A Protein Therapeutic for Treating Osteoarthritis?
Poster Presentation. Segal North American Osteoarthritis Workshop. May 24, 2008, Chicago, Illinois.
49. Marc Zack, Anne-Marie Malfait and Micky Tortorella. A Disintegrin and
Metalloproteinase-8 (ADAM8): The identification and characterization of
a novel target for the treatment of arthritic disorders. Podium
Presentation. Midwest Connective Tissue Workshop. May 7-8, 2010,
Chicago, Illinois.
50. Micky D. Tortorella, Christopher B. Little, Ashutosh Barai, Susan
Smith, Lily Song, Charles Anglin, Ruth TenBrink, John Freskos, Alfredo G.
Tomasselli and Anne-Marie Malfait. Healthy minds, healthy joints:
Defining a new role for BACE-1 in cartilage erosion. Poster Presentation.
Osteoarthritis Research Society International Meeting. September 23-26,
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2010, Brussels, Belgium.
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