The Apte Lab conducts fundamental research on extracellular matrix and the proteases that remodel it.
Why? Because extracellular matrix is the basis for existence of multicellular life forms. It provides the structural scaffold of every tissue and is a major regulatory influence on cells. We study it at the organ, tissue, cell and molecular scale, and investigate how protease dysregulation leads to a host of human conditions.
Matrix is continuously remodeled by balanced matrix production and removal by matrix degrading proteases. Matrix remodeling is crucial for morphogenesis, tissue repair and regeneration and is abnormal in many cardiovascular disorders, degenerative disorders such as osteoarthritis, cancer, fibrosis, birth defects and inherited connective tissue disorders. The ADAMTS proteases, a focus of our laboratory, are important participants in this process.
Some of our diverse research activities are highlighted below:
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The laboratory has received support from several NIH institutes, including NIAMS, NEI, NICHD and the NIH-NHLBI Program of Excellence in Glycosciences, the Marfan Foundation, Arthritis Foundation and Sabrina's Foundation. Our current research is supported by the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association and NIH-NHLBI.
Extracellular matrix (ECM) is the intricate mesh-like material that surrounds all cells and provides a scaffold for tissue and organ architecture. ECM is one of the most important determinants of whether organs form properly and function normally. For this reason, ECM proteostasis is carefully controlled and as part of this proteostatic process, ECM undergoes constant remodeling by proteases. Theabnormal activity of proteases is a major contributor to adult-onset disorders such as osteoarthritis and aortic aneurysms, and to most adult and pediatric cancers.Proteases are not utilized solely for tissue maintenance, however, and also have a major role in organ development in the embryo. We have discovered that several protease mutations can lead to common birth defects. This relevance to adult and pediatric disorders has motivated our broad interest in ECM and ECM-remodeling proteases.
Research on the ADAMTS proteases is a major emphasis of the laboratory because of their high significance for embryonic development and adult diseases. We investigate how their mutations lead to birth defects affecting the heart, blood vessels, brain, eyes, face and limbs. Our research is also relevant to maternal-fetal health and inherited human connective tissue disorders such as Marfan syndrome and the acromelic dysplasias. Among acquired human disorders, we investigate osteoarthritis, aortic aneurysms, cancer and heart failure. The laboratory makes intensive use of a proteomics strategy termed degradomics to identify protease substrates and define the proteolytic landscape of diseased human tissues.
To access our work, please click on the publications tab at the top of this page for publications or visit Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/.
Our research group studies extracellular matrix, the intricate, mesh-like substance that surrounds all cells other than blood cells, and determines the structure of tissues and organs. We are especially interested in proteases, which are enzymes that break down proteins, and how they alter the extracellular matrix. Proteolytic breakdown of the matrix is necessary for normal organ formation and function, but inadequate or excessive matrix or protease activity contributes to impaired organ function in nearly all medical conditions. We are applying the discoveries we make to common illnesses such as osteoarthritis, aortic aneurysms, heart disease and cancer, where matrix and proteases are unusually important and to genetic disorders and birth defects affecting the heart, eyes, and limbs.
Suneel Apte graduated from medical school at Bombay University. He interrupted his clinical training as an orthopaedic surgeon to obtain the D. Phil degree at the University of Oxford (Mentor: John Kenwright), where he was a Rhodes Scholar. He subsequently trained as a post-doctoral fellow with Bjorn Olsen at Harvard Medical School. His current interest is integrating genetics and cell biology with proteomics at the systems biology level to advance understanding of tissue turnover during embryonic development and a variety of human disorders.
Sumit Bhutada obtained his PhD at the National Institute for Research in Reproductive Health, Mumbai, India working with Geetanjali Sachdeva. He trained in the area of female infertility resulting from endometrial factors, using proteomics as the principal technology. He has experience in gel-based and gel-free proteomics techniques and data analysis. He is currently involved in implementation of shotgun and terminomics analysis of complex samples to address critical questions in developmental biology and human disorders.
Catelyn Clark is a recent graduate of Saint Mary’s College and is working towards her master's in data science. She has an interest in birth defects and genetic disorders and is using mouse genetics, histology, and microscopy to further this interest.
Daniel Martin obtained his PhD in cell and molecular biology at the University of South Florida, in Tampa, with mentorship by Stanley M. Stevens Jr. and Brant Burkhardt. His background is in applied mass spectrometry-based proteomics techniques and analysis. His current research uses proteomics to investigate cardiovascular diseases using a combination of iTRAQ, and dimethyl labeling for both quantitative shotgun proteomics and terminal amine isotope labeling of substrates (TAILS). These methods provide insight into the proteome, the natural N-termini, and the proteolytic products present in the sample.
Publications in 2022
Mead TJ, Bhutada S, Martin DR, Apte SS. Proteolysis: a key post-translational modification regulating proteoglycans. Am J Physiol Cell Physiol. 2022 Jul 4. doi: 10.1152/ajpcell.00215.2022. Online ahead of print.PMID: 35785985 Review.
Mead, TJ, Martin DR, Wang LW, Cain SA, Gulec C, Cahill E, Mauch J, Reinhardt, DR, Lo C, Baldock C, Apte SS. Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development. eLife 2022;11:e71142 DOI: 10.7554/eLife.71142
Forward and reverse degradomics defines the proteolytic landscape of human knee osteoarthritic cartilage and the role of the serine protease HtrA1. Osteoarthritis Cartilage. 2022 Mar 24:S1063-4584(22)00691-4. doi: 10.1016/j.joca.2022.02.622 (Featured in Editorial https://www.oarsijournal.com/article/S1063-4584(22)00698-7/fulltext)
Kuwabara JT, Hara A, Heckl JR, Peña B, Bhutada S, DeMaris R, Ivey MJ, DeAngelo LP, Liu X, Park J, Jahansooz JR, Mestroni L, McKinsey TA, Apte SS, Tallquist MD. Regulation of extracellular matrix composition by fibroblasts during perinatal cardiac maturation. J Mol Cell Cardiol. 2022 May 13;169:84-95. doi: 10.1016/j.yjmcc.2022.05.003.
Foulcer SJ, Day AJ, Apte SS. Isolation and Purification of Versican and Analysis of Versican Proteolysis. Methods Mol Biol. 2022;2303:559-578. doi: 10.1007/978-1-0716-1398-6_43
Perry WJ, Grunenwald CM, Van de Plas R, Witten JC, Martin DR, Apte SS, Cassat JE, Pettersson GB, Caprioli RM, Skaar EP, Spraggins JM. Visualizing Staphylococcus aureus pathogenic membrane modification within the host infection environment by multimodal imaging mass spectrometry. Cell Chem Biol. 2022 May 27:S2451-9456(22)00196-9. doi: 10.1016/j.chembiol.2022.05.004.
Publications in 2021
Martin DR, Santamaria S, Koch CD, Ahnström J, Apte SS. Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach. J Proteomics. 2021 Aug 24:104358. doi: 10.1016/j.jprot.2021.104358. Online ahead of print.
Santamaria S, Martin DR, Dong X, Yamamoto K, Apte SS, Ahnström J. Post-Translational Regulation And Proteolytic Activity Of The Metalloproteinase Adamts8. J Biol Chem. 2021 Oct 20:101323. doi: 10.1016/j.jbc.2021.101323. Online ahead of print.
Rypdal KB, Erusappan PM, Melleby AO, Seifert DE, Palmero S, Strand ME, Tønnessen T, Dahl CP, Almaas V, Hubmacher D, Apte SS, Christensen G, Lunde IG. The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts. Sci Rep. 2021 Oct 5;11(1):19757. doi: 10.1038/s41598-021-99032-2.
Apte SS. The Pivotal Role of Versican Turnover by ADAMTS Proteases in Mammalian Reproduction and Development. In Proteoglycans in Stem Cells. From Development to Cancer. Götte, M, Forsberg-Nilsson, K (Eds.), Springer 2021, ISBN 978-3-030-73452-7.
Nandadasa S, Burin des Rozier C, Koch C, Tran-Lundmark K, Dours-Zimmermann MT, Zimmermann DR, Valleix S, Apte SS. A new mouse mutant with cleavage-resistant versican and isoform-specific versican mutants demonstrate that proteolysis at the Glu441-Ala442 peptide bond in the V1 isoform is essential for interdigital web regression. Matrix Biology Plus, 2021, May 14;10:100064. doi: 10.1016/j.mbplus.2021.100064.
Nandadasa S, O'Donnell A, Murao A, Yamaguchi Y, Midura RJ, Olson L, Apte SS. The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ hematoendothelial progenitors. Matrix Biol. 2021 Mar;97:40-57. doi: 10.1016/j.matbio.2021.01.002.
Arechederra M, Bazai SK, Abdouni A, Sequera C, Mead TJ, Richelme S, Daian F, Audebert S, Dono R, Lozano A, Gregoire D, Hibner U, Allende DS, Apte SS, Maina F. ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma. J Hepatol. 2021 Apr;74(4):893-906. doi: 10.1016/j.jhep.2020.11.008.
Witten JC, Tan CD, Rodriguez ER, Shrestha NK, Gordon SM, Hussain ST, Apte SS, Unai S, Blackstone EH, Pettersson GB. Invasive Aortic Valve Endocarditis: Clinical and Tissue Findings from a Prospective Investigation. Ann Thorac Surg. 2021 Apr 8;S0003-4975(21)00651-2. doi: 10.1016/j.athoracsur.2021.03.072.
Balic Z, Misra S, Willard B, Reinhardt DP, Apte SS, Hubmacher D. Alternative splicing of the metalloprotease ADAMTS17 spacer regulates secretion and modulates autoproteolytic activity. FASEB J. 2021 Feb;35(2):e21310. doi: 10.1096/fj.202001120RR.
Publications in 2020
Nandadasa S, Szafron JM, Pathak V, Murtada S-I, Kraft CM, O ’ Donnell A, Norvik C, Hughes C, Caterson B, Domowicz MS, Schwartz NB, Tran-Lundmark K, Veigl M, Sedwick D, Philipson EH, Humphrey JD, Apte SS. Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth. Elife. 2020 Sep 10;9:e60683. doi: 10.7554/eLife.60683. Accompanying Commentary: https://elifesciences.org/articles/63128
Ataca D, Aouad P, Constantin C, Laszlo C, Beleut M, Shamseddin M, Rajaram RD, Jeitziner R, Mead TJ, Caikovski M, Bucher P, Ambrosini G, Apte SS, Brisken C. The secreted protease ADAMTS18 links hormone action to activation of the mammary stem cell niche. Nat Commun. 2020 Mar 26;11(1):1571. doi: 10.1038/s41467-020-15357-y.
Zhang A, Berardinelli SJ, Leonhard-Melief C, Vasudevan D, Liu TW, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS. O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations. J Biol Chem. 2020 Sep 10:jbc.RA120.014557. doi: 10.1074/jbc.RA120.014557. Online ahead of print.
Evans DR, Green JS, Fahiminiya S, Majewski J, Fernandez BA, Deardorff MA, Johnson GJ, Whelan JH, Hubmacher D, Apte SS; Care4Rare Canada Consortium, Woods MO. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features. Sci Rep. 2020 Jul 2;10(1):10827. doi: 10.1038/s41598-020-66978-8
Koch CD, Lee CM, Apte SS. Aggrecan in Cardiovascular Development and Disease. J Histochem Cytochem. 2020 Sep 1:22155420952902. doi: 10.1369/0022155420952902.
Koch CD, Apte SS. Characterization of Proteoglycanomes by Mass Spectrometry. In, S. Ricard-Blum (ed.) Extracellular Matrix Omics, In the series, Biology of Extracellular Matrix, pp69-82. ISBN 978-3-030-58329-3 7. SpringerNature Switzerland AG 2020.https://doi.org/10.1007/978-3-030-58330-9_4
Apte SS. ADAMTS Proteins: Concepts, Challenges, and Prospects. Methods Mol Biol. 2020;2043:1-12. doi: 10.1007/978-1-4939-9698-8_1. Review.
Mead TJ, Apte SS.Visualization and Quantification of Pericellular Matrix. Methods Mol Biol. 2020;2043:261-264. doi: 10.1007/978-1-4939-9698-8_21.
Mead TJ, Apte SS.Expression Analysis by RNAscope™ In Situ Hybridization. Methods Mol Biol. 2020;2043:173-178. doi: 10.1007/978-1-4939-9698-8_14.
Publications in 2019
Wang LW, Nandadasa S, Annis DS, Dubail J, Mosher DF, Willard BB, Apte SS. A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9) regulates fibronectin fibrillogenesis and turnover. J Biol Chem, 2019,294:9924-9936. doi: 10.1074/jbc.RA118.006479
Nandadasa, S, Kraft, CM, O’Donnell, A, Wang, LW, O’Donnell, A, Patel, R, Gee HY, Grobe, K, Cox, TC, Hildebrandt F and Apte, SS. Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis. Nature Communications, (2019) 10:953 | https://doi.org/10.1038/s41467-019-08520-7
Choi YJ, Halbritter J, Braun DA, Schueler M, Schapiro D, Rim JH, Nandadasa S, Choi WI, Widmeier E, Shril S, Körber F, Sethi SK, Lifton RP, Beck BB, Apte SS, Gee HY,Hildebrandt F. Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. Am J Hum Genet. 2019 104:45-54. doi: 10.1016/j.ajhg.2018.11.003.
Wang LW, Kutz WE, Mead TJ, Beene LC, Singh S, Jenkins MW, Reinhardt DP, Apte SS. Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage. Matrix Biol. 2019, 77:117-128. pii: S0945-053X(18)30253-1. doi: 10.1016/j.matbio.2018.09.004.
Jensen LD, Hot B, Ramsköld D, Germano RFV, Yokota C, Giatrellis S, Lauschke VM, Hubmacher D, Li MX, Hupe M, Arnold TD, Sandberg R, Frisén J, Trusohamn M, Martowicz A, Wisniewska-Kruk J, Nyqvist D, Adams RH, Apte SS, Vanhollebeke B, Stenman JM, Kele J. Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling. Arterioscler Thromb Vasc Biol. 2019 39:1432-1447. doi: 10.1161/ATVBAHA.119.312388.
Santamaria S, Yamamoto K, Teraz-Orosz A, Koch C, Apte SS, de Groot R, Lane DA, Ahnström J. Exosites in Hypervariable Loops of ADAMTS Spacer Domains control Substrate Recognition and Proteolysis. Sci Rep. 2019 Jul 29;9(1):10914. doi: 10.1038/s41598-019-47494-w
Holdener BC, Percival CJ, Grady RC, Cameron DC, Berardinelli SJ, Zhang A, Neupane S, Takeuchi M, Jimenez-Vega JC, Uddin SMZ, Komatsu DE, Honkanen R, Dubail J, Apte SS, Sato T, Narimatsu H, McClain SA, Haltiwanger RS. ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in a mouse model of Peters Plus Syndrome. Hum Mol Genet. 2019 Oct 10. pii: ddz225. doi: 10.1093/hmg/ddz225. [Epub ahead of print]
Graae AS, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H, Fritsche A, Wellner N, Sulek K, Kjolby M, Backe MB, Chubanava S, Prats C, Serup AK, Birk JB, Dubail J, Gillberg L, Vienberg SG, Nykjær A, Kiens B, Wojtaszewski JFP, Larsen S, Apte SS, Häring HU, Vaag A, Zethelius B, Pedersen O, Treebak JT, Hansen T, Holst B.ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations. Diabetes. 68(3):502-514. doi: 10.2337/db18-0418.
Publications in 2018
Mead TJ, Du Y, Nelson CM, Gueye N-A, Drazba J, Dancevic CM, Vankemmelbeke M, Buttle DJ, Apte SS. ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation. Cell Reports. 2018, 23; 2, 485-498.
Mead TJ, McCulloch DR, Ho JC, Du Y, Adams SM, Birk DE, Apte SS. The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification. JCI Insight. 2018 April5;3(7). pii: 92941. doi: 10.1172/jci.insight.92941
Cikach FS, Koch CD, Mead TJ, Galatioto J, Willard BB, Emerton KB, Eagleton MJ, Blackstone EH, Ramirez F, Roselli EE, Apte SS. Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection. JCI Insight. 2018 Mar 8;3(5). pii: 97167. doi: 10.1172/jci.insight.97167.
Prins, B. , Mead, T.J. (joint first authors) et al. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol 2018, 19:87. https://doi.org/10.1186/s13059-018-1457-6
Schnellmann R, Sack R, Hess D, Annis DS, Mosher DF, Apte SS, Chiquet-Ehrismann R. A selective extracellular matrix proteomics approach identifies fibronectin proteolysis by ADAMTS16 and its impact on spheroid morphogenesis. Mol Cell Proteomics. 2018 Apr 18. pii: mcp.RA118.000676. doi: 10.1074/mcp.RA118.000676. [Epub ahead of print]
Aviram R, Zaffryar-Eilot S, Hubmacher D, Grunwald H, Mäki JM, Myllyharju J, Apte SS, Hasson P. Interactions between lysyl oxidases and ADAMTS proteins suggest a novel crosstalk between two extracellular matrix families. Matrix Biol. 2018 May 11. pii: S0945-053X(17)30448-1. doi: 10.1016/j.matbio.2018.05.003.
A sampling of research publications from 2017 and earlier:
1. Hubmacher D, Schneider M, Berardinelli S, Takeuchi H, Willard B, Reinhardt DH, Haltiwanger R, and Apte SS. Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Scientific Reports, 2017;7:41871. doi: 10.1038/srep41871.
2. Dubail, J, Vasudevan, D, Wang, LW, Earp, SE, Jenkins, MW, Haltiwanger, RS, and Apte SS. Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome. Scientific Reports. 2016. 6:33974. doi: 10.1038/srep33974.
3. Nandadasa, S., Nelson, C.M., Apte, SS. ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation. Cell Reports 11:1519-28, 2015
4. Enomoto, H., Nelson, C., Somerville, R.P.T., Mielke, K., Dixon, L., Powell, K., Apte, S.S. Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development, 2010, 37:4029-38.
5. McCulloch, D.R., Nelson, C.M., Dixon, L.J., Silver D.L., Wylie, J.D., Lindner, V., Sasaki, T., Cooley, M.A., Argraves, W.S. and Apte, S.S. ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Developmental Cell 2009, 17:687-98. PMCID:PMC2780442.
Apte SS. ADAMTS proteins: Concepts, Challenges and Prospects. Methods Mol Biol. 2020;2043:1-12. doi: 10.1007/978-1-4939-9698-8_1.
Reviews, technical reports and commentaries
2. Apte, SS. Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis. Biochem J. 2016 Jan 1;473(1):e1-e4
3. Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics.Matrix Biol. 44-46:24-37 2015
4. Foulcer SJ, Day AJ, Apte SS. Isolation and purification of versican and analysis of versican proteolysis. Methods Mol Biol. 1229:587-604, 2015
5. Nandadasa S, Foulcer S, Apte SS. The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol. 2014, 35:34-41, 2014.
1. Apte, SS. Chapter 259. Connective Tissue Structure and Function. ed. Goldman L, and Shafer, A.I., Goldman-Cecil Textbook of Medicine, Twenty-Fifth Edition, Elsevier, New York, 2016, ISBN 9781455750177
2. Apte SS. ADAMTS proteases: Mediators of physiological and pathogenic extracellular proteolysis, in Bradshaw, R., and Stahl, P, eds, Encyclopedia of Cell Biology, Elsevier, New York, 2015, ISBN 9780123944474
3. Apte, SS. Chapter 2. Overview of the ADAMTS superfamily, in Rodgers, G., ed, ADAMTS13: Biology and Disease, Springer, New York, 2015, ISBN 9783319087160
4. Traboulsi I, and Apte SS. Chapter 43. Ectopia Lentis and Associated Systemic Disease, in Traboulsi, I., ed, Genetic Diseases of the Eye, Second Edition, Oxford University Press, USA, 2012, ISBN 9780195326147
Additional publications from our laboratory are obtainable from Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/
Researchers have discovered that umbilical cord arteries contain components that naturally promote narrowing at birth, and ensure a sequence in which the arteries close before the vein, supporting delayed cord clamping following delivery in most uncomplicated deliveries.
A team of researchers, led by the Department of Biomedical Engineering, found that differences in the protein makeup of vegetations may help to identify the pathogen of infective endocarditis and cast new light upon the deadly disease.
The Apte Laboratory
Lerner Research Institute
9500 Euclid Avenue
Mail Code: ND20
Cleveland, OH 44195