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Faculty Affairs: Faculty Interests Database Andrzej Fertala, PhD

Orthopaedic Surgery
Thomas Jefferson University
Jefferson Medical College
Department of Orthopaedic Surgery

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Mailing Address Contact Information
1015 Walnut str.
Philadelphia, Pennsylvania 19107
United States
Phone: 215-503-0113
Expertise and Research Interests
My primary research activities involve the area of extracellular matrix. In particular, my studies focus on
(i) identifying pathomechanisms of heritable diseases of connective tissues caused by mutations in collagen
genes, (ii) technologies to produce novel collagen-like proteins for biomedical applications, and (iii)
developing novel approaches to limit excessive fibrosis.
In the studies on the molecular basis of the heritable diseases caused by mutations in collagenous
proteins, my studies place a main emphasis on (i) osteogenesis imperfecta caused by mutations in collagen
I, (ii) spondyloepiphyseal displasias caused by mutations in collagen II, and (iii) on epidermolysis bullosa
caused by mutations in collagen VII.
In addition to the studies on pathomechanisms of heritable diseases of connective tissues, my work
contributed significantly to developing novel technologies for the production of human recombinant collagens
for a number of biomedical applications. As animal-derived collagens and gelatin, at present widely used in
biomedical and pharmaceutical fields, have the potential to transmit animal-derived diseases, the ability to
produce recombinant human collagens and gelatin is very attractive. The high value and the potential
applicability of recombinant human collagens are reflected by an approved patent and its licensing by
Thomas Jefferson University to a commercial company. In addition to already established technologies, I
continue developing new approaches to the rational engineering of collagenous proteins for biomedical
In response to the need for novel therapies for fibrotic diseases, my laboratory has recently initiated
studies on novel approaches to limit excessive fibrosis. These new approaches are built on my discoveries of
processes that govern the formation of collagen fibrils. As this process is fundamental for the formation of
fibrotic deposits, my concept is that, by inhibiting the formation of collagen fibrils, it will be possible to limit
fibrosis. If experimentally confirmed, this novel concept may lead to developing novel inhibitors of fibrotic
processes occurring in keloids, hypertrophic scarring, and others.
Other Expertise
Technical Collaboration
I have a technical collaboration with TestResources. They have designed and engineered knee torque
measurement test machine designed for testing the stiffness of rabbit knee joints.
Industrial Relevance

1. Prockop, D.J., L. Ala-Kokko, A. Fertala, A. Sieron, K.I. Kivirikko, A. Geddis, T. Pihlajaniemi, Synthesis of
human procollagens and collagens in recombinant DNA systems. U.S. Patent Number 5,405,757, 1995 (Patent
licensed by TJU to a biotech company; FibroGen).

2. Prockop, D.J., A. Fertala, Inhibitors of collagen assembly. U.S. Patent Number 6,472,504. 2002.

3. Fertala, A., F. Ko, Collagen or collagen-like peptide containing polymeric matrices. U.S. Patent Number
6,753,311, 2004.
collagen; extracellular matrix; recombinant collagen; fibrosis
  • 1. Fertala A, Westerhausen A, Morris G, Rooney JE, Prockop DJ: Two cysteine substitutions in
  • procollagen I: a glycine replacement near the N-terminus of alpha 1(I) chain causes lethal osteogenesis
  • imperfecta and a glycine replacement in the alpha 2(I) chain markedly destabilizes the triple helix, Biochem J
  • 1993, 289:195-199.
  • 2. Sieron AL, Fertala A, Ala-Kokko L, Prockop DJ: Deletion of a large domain in recombinant human
  • procollagen II does not alter the thermal stability of the triple helix, J Biol Chem 1993, 268:21232-21237
  • 3. Fertala A, Sieron AL, Ganguly A, Li SW, Ala-Kokko L, Anumula KR, Prockop DJ: Synthesis of
  • recombinant human procollagen II in a stably transfected tumour cell line (HT1080), Biochem J 1994, 298:31-
  • 37
  • 4. Fertala A, Sieron AL, Hojima Y, Ganguly A, Prockop DJ: Self-assembly into fibrils of collagen II by
  • enzymic cleavage of recombinant procollagen II. Lag period, critical concentration, and morphology of fibrils
  • differ from collagen I, J Biol Chem 1994, 269:11584-11589
  • 5. Ganguly A, Smelt S, Mewar R, Fertala A, Sieron AL, Overhauser J, Prockop DJ: Targeted insertions of
  • two exogenous collagen genes into both alleles of their endogenous loci in cultured human cells: the
  • insertions
  • are directed by relatively short fragments containing the promoters and the 5' ends of the genes, Proc Natl
  • Acad Sci U S A 1994, 91:7365-7369
  • 6. Ala-Kokko L, Yuan CM, Le Guellec D, Franc S, Fertala A, Khillan JS, Sokolov BP, Prockop DJ: A 1.9-
  • Kb
  • 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in
  • tissues of transgenic mice that normally express only the COL1A1 gene, Ann N Y Acad Sci 1996, 785:202-
  • 203
  • 7. Fertala A, Ala-Kokko L, Prockop DJ: Characterization of recombinant human collagen II with Arg519-to-
  • Cys substitution, Ann N Y Acad Sci 1996, 785:251-253
  • 8. Fertala A, Holmes DF, Kadler KE, Sieron AL, Prockop DJ: Assembly in vitro of thin and thick fibrils of
  • collagen II from recombinant procollagen II. The monomers in the tips of thick fibrils have the opposite
  • orientation from monomers in the growing tips of collagen I fibrils, J Biol Chem 1996, 271:14864-14869
  • 9. Jagodzinski PP, Wustner J, Kmieciak D, Wasik TJ, Fertala A, Sieron AL, Takahashi M, Tsuji T,
  • Mimura
  • T, Fung MS, Gorny MK, Kloczewiak M, Kaneko Y, Kozbor D: Role of the V2, V3, and CD4-binding domains
  • of
  • GP120 in curdlan sulfate neutralization sensitivity of HIV-1 during infection of T lymphocytes, Virology 1996,
  • 226:217-227
  • 10. Li SW, Sieron AL, Fertala A, Hojima Y, Arnold WV, Prockop DJ: The C-proteinase that processes
  • procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-
  • 1,
  • Proc Natl Acad Sci U S A 1996, 93:5127-5130
  • 11. Arnold WV, Sieron AL, Fertala A, Bachinger HP, Mechling D, Prockop DJ: A cDNA cassette system
  • for
  • the synthesis of recombinant procollagens. Variants of procollagen II lacking a D-period are secreted as
  • triple-
  • helical monomers, Matrix Biol 1997, 16:105-116
  • 12. Fertala A, Ala-Kokko L, Wiaderkiewicz R, Prockop DJ: Collagen II containing a Cys substitution for arg-
  • alpha1-519. Homotrimeric monomers containing the mutation do not assemble into fibrils but alter the self-
  • assembly of the normal protein, J Biol Chem 1997, 272:6457-6464
  • 13. Zafarullah K, Brown EM, Kuivaniemi H, Tromp G, Sieron AL, Fertala A, Prockop DJ: Synthesis and
  • conformational properties of a recombinant C-propeptide of human type III procollagen, Matrix Biol 1997,
  • 16:201-209.
  • 14. Zafarullah K, Sieron AL, Fertala A, Tromp G, Kuivaniemi H, Prockop DJ: A recombinant homotrimer of
  • type I procollagen that lacks the central two D-periods. The thermal stability of the triple helix is decreased
  • by
  • 2 to 4 degrees C, Matrix Biol 1997, 16:245-253.
  • 15. Arnold WV, Fertala A, Sieron AL, Hattori H, Mechling D, Bachinger HP, Prockop DJ: Recombinant
  • procollagen II: Deletion of D period segments identifies sequences that are required for helix stabilization and
  • generates a temperature-sensitive N-proteinase cleavage site, J Biol Chem 1998, 273:31822-31828
  • 16. Prockop DJ, Fertala A: Inhibition of the self-assembly of collagen I into fibrils with synthetic peptides.
  • Demonstration that assembly is driven by specific binding sites on the monomers, J Biol Chem 1998,
  • 273:15598-15604
  • 17. Prockop DJ, Fertala A: The collagen fibril: the almost crystalline structure, Journal of structural biology
  • 1998, 122:111-118
  • 18. Adachi E, Katsumata O, Yamashina S, Prockop DJ, Fertala A: Collagen II containing a Cys
  • substitution
  • for Arg-alpha1-519. Analysis by atomic force microscopy demonstrates that mutated monomers alter the
  • topography of the surface of collagen II fibrils, Matrix Biol 1999, 18:189-196
  • 19. Annunen S, Yao-Bin L, Jaalinoja J, Ylostalo J, Philajamaa T, Ala-Kokko L, Fertala A: A Trp substitution
  • for Gly-alpha2-326 in collagen IX changesthe affinity to collagen II and results in the recognition of non-
  • specific
  • binding sites. Edited by Philadelphia, PA, 2000, p.
  • 20. Green lK, Cabral WA, Fertala A, Korkko J, Forlino A, Marini JC: COL1A1 IVS A4+C mutation causes
  • splicing out of exon 41 and confirms importance of this region for fibril assembly., Am J Hum Genet 2000,
  • 67:369
  • 21. Yuan CM, Ala-Kokko L, Le Guellec D, Franc S, Fertala A, Khillan JS, Sokolov BP, Prockop DJ: Lack
  • of
  • a phenotype in transgenic mice aberrantly expressing COL2A1 mRNA because of highly selective post-
  • transcriptional down-regulation, Biochem J 2000, 345 Pt 2:377-384
  • 22. Arita M, Adachi E, Jimenez S, Fertala A: Collagen II containing a Cys for Arg-alpha1-519: Abnormal
  • interactions with collagen IX in vitro and alterations in skeletal development in transgenic mice expressing the
  • mutated human gene. Edited by Washington, DC, USA, W.B. Saunders, 2001, p. S16
  • 23. Fertala A, Han WB, Ko FK: Mapping critical sites in collagen II for rational design of gene- engineered
  • proteins for cell-supporting materials, Journal of biomedical materials research 2001, 57:48-58.
  • 24. Fertala A, Sieron AL, Adachi E, Jimenez SA: Collagen II containing a Cys substitution for Arg-alpha1-
  • 519: abnormal interactions of the mutated molecules with collagen IX, Biochemistry 2001, 40:14422-14428.
  • 25. Li SW, Arita M, Fertala A, Bao Y, Kopen GC, Langsjo TK, Hyttinen MM, Helminen HJ, Prockop DJ:
  • Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male
  • sterility, Biochem J 2001, 355:271-278
  • 26. Arita M, Li SW, Kopen G, Adachi E, Jimenez SA, Fertala A: Skeletal abnormalities and ultrastructural
  • changes of cartilage in transgenic mice expressing a collagen II gene (COL2A1) with a Cys for Arg-alpha1-
  • 519
  • substitution, Osteoarthritis Cartilage 2002, 10:808-815
  • 27. Cabral WA, Fertala A, Green LK, Korkko J, Forlino A, Marini JC: Procollagen with skipping of alpha 1(I)
  • exon 41 has lower binding affinity for alpha 1(I) C-telopeptide, impaired in vitro fibrillogenesis, and altered fibril
  • morphology, J Biol Chem 2002, 277:4215-4222.
  • 28. Sieron AL, Louneva N, Fertala A: Site-specific interaction of bone morphogenetic protein 2 with
  • procollagen ii, Cytokine 2002, 18:214-221.
  • 29. Sun YL, Luo ZP, Fertala A, An KN: Direct quantification of the flexibility of type I collagen monomer,
  • Biochem Biophys Res Commun 2002, 295:382-386.
  • 30. Colombo M, Brittingham RJ, Klement JF, Majsterek I, Birk DE, Uitto J, Fertala A: Procollagen VII self-
  • assembly depends on site-specific interactions and is promoted by cleavage of the NC2 domain with
  • procollagen C-proteinase, Biochemistry 2003, 42:11434-11442
  • 31. Majsterek I, McAdams E, Adachi E, Dhume ST, Fertala A: Prospects and limitations of the rational
  • engineering of fibrillar collagens, Protein Sci 2003, 12:2063-2072
  • 32. McGinley JC, Heller JE, Fertala A, Gaughan JP, Kozin SH: Biochemical composition and histologic
  • structure of the forearm interosseous membrane, J Hand Surg [Am] 2003, 28:503-510
  • 33. Rouan F, Lo CW, Fertala A, Wahl M, Jost M, Rodeck U, Uitto J, Richard G: Divergent effects of two
  • sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro, Exp Dermatol 2003,
  • 12:191-197
  • 34. Brennan D, Hu Y, Kljuic A, Choi Y, Joubeh S, Bashkin M, Wahl J, Fertala A, Pulkkinen L, Uitto J,
  • Christiano AM, Panteleyev A, Mahoney MG: Differential structural properties and expression patterns
  • suggest
  • functional significance for multiple mouse desmoglein 1 isoforms, Differentiation; research in biological
  • diversity
  • 2004, 72:434-449
  • 35. Kisiel DG, Calvete JJ, Katzhendler J, Fertala A, Lazarovici P, Marcinkiewicz C: Structural determinants
  • of the selectivity of KTS-disintegrins for the alpha1beta1 integrin, FEBS Lett 2004, 577:478-482
  • 36. Leitinger B, Steplewski A, Fertala A: The D2 period of collagen II contains a specific binding site for the
  • human discoidin domain receptor, DDR2, J Mol Biol 2004, 344:993-1003
  • 37. Steplewski A, Ito H, Rucker E, Brittingham RJ, Alabyeva T, Gandhi M, Ko FK, Birk DE, Jimenez SA,
  • Fertala A: Position of single amino acid substitutions in the collagen triple helix determines their effect on
  • structure of collagen fibrils, Journal of structural biology 2004, 148:326-337
  • 38. Steplewski A, Majsterek I, McAdams E, Rucker E, Brittingham RJ, Ito H, Hirai K, Adachi E, Jimenez
  • SA, Fertala A: Thermostability gradient in the collagen triple helix reveals its multi-domain structure, J Mol
  • Biol
  • 2004, 338:989-998
  • 39. Sun YL, Luo ZP, Fertala A, An KN: Stretching type II collagen with optical tweezers, J Biomech 2004,
  • 37:1665-1669
  • 40. Brittingham R, Colombo M, Ito H, Steplewski A, Birk DE, Uitto J, Fertala A: Single Amino Acid
  • Substitutions in Procollagen VII Affect Early Stages of Assembly of Anchoring Fibrils, J Biol Chem 2005,
  • 280:191-198
  • 41. Fujimoto N, Terlizzi J, Brittingham R, Fertala A, McGrath JA, Uitto J: Extracellular matrix protein 1
  • interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2, Biochem
  • Biophys
  • Res Commun 2005, 333:1327-1333
  • 42. Ito H, Rucker E, Steplewski A, McAdams E, Brittingham RJ, Alabyeva T, Fertala A: Guilty by
  • association: some collagen II mutants alter the formation of ECM as a result of atypical interaction with
  • fibronectin, J Mol Biol 2005, 352:382-395
  • 43. Steplewski A, Brittingham R, Jimenez SA, Fertala A: Single amino acid substitutions in the C-terminus
  • of collagen II alter its affinity for collagen IX, Biochem Biophys Res Commun 2005, 335:749-755
  • 44. Wang H, Fertala A, Ratner BD, Sage EH, Jiang S: Identifying the SPARC binding sites on collagen I
  • and
  • procollagen I by atomic force microscopy, Analytical chemistry 2005, 77:6765-6771
  • 45. Brittingham R, Uitto J, Fertala A: High-affinity binding of the NC1 domain of collagen VII to laminin 5
  • and
  • collagen IV, Biochem Biophys Res Commun 2006, 343:692-699
  • 46. Fujimoto N, Terlizzi J, Aho S, Brittingham R, Fertala A, Oyama N, McGrath JA, Uitto J: Extracellular
  • matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein
  • interactions, Exp Dermatol 2006, 15:300-307
  • 47. Ito H, Steplewski A, Alabyeva T, Fertala A: Testing the utility of rationally engineered recombinant
  • collagen-like proteins for applications in tissue engineering, Journal of biomedical materials research Part A
  • 2006, 76:551-560
  • 48. Cabral WA, Makareeva E, Letocha AD, Scribanu N, Fertala A, Steplewski A, Keene DR, Persikov AV,
  • Leikin S, Marini JC: Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is
  • associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype, Hum Mutat 2007, 28:396-405
  • 49. Rodeck U, Fertala A, Uitto J: Anchorless keratinocyte survival: an emerging pathogenic mechanism for
  • squamous cell carcinoma in recessive dystrophic epidermolysis bullosa, Exp Dermatol 2007, 16:465-467
  • 50. Steplewski A, Hintze V, Fertala A: Molecular basis of organization of collagen fibrils, Journal of
  • structural
  • biology 2007, 157:297-307
  • 51. Twardowski T, Fertala A, Orgel JP, San Antonio JD: Type I collagen and collagen mimetics as
  • angiogenesis promoting superpolymers, Curr Pharm Des 2007, 13:3608-3621
  • 52. Chung HJ, Steplewski A, Chung KY, Uitto J, Fertala A: Collagen fibril formation. A new target to limit
  • fibrosis, J Biol Chem 2008, 283:25879-25886
  • 53. Hintze V, Steplewski A, Ito H, Jensen DA, Rodeck U, Fertala A: Cells expressing partially unfolded
  • R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo
  • apoptosis,
  • Hum Mutat 2008, 29:841-851
  • 54. Sweeney SM, Orgel JP, Fertala A, McAuliffe JD, Turner KR, Di Lullo GA, Chen S, Antipova O, Perumal
  • S, Ala-Kokko L, Forlino A, Cabral WA, Barnes AM, Marini JC, San Antonio JD: Candidate cell and matrix
  • interaction domains on the collagen fibril, the predominant protein of vertebrates, J Biol Chem 2008,
  • 283:21187-21197
  • 55. Chung HJ, Jensen DA, Gawron K, Steplewski A, Fertala A: R992C (p.R1192C) Substitution in collagen
  • II
  • alters the structure of mutant molecules and induces the unfolded protein response, J Mol Biol 2009,
  • 390:306-
  • 318
  • 56. Chung HJ, Steplewski A, Uitto J, Fertala A: Fluorescent protein markers to tag collagenous proteins:
  • the
  • paradigm of procollagen VII, Biochem Biophys Res Commun 2009, 390:662-666
  • 57. Al Ahmad A, Lee B, Stack J, Parham C, Campbell J, Clarke D, Fertala A, Bix GJ: Endostatin binds
  • nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro, Brain Res 2010,
  • 1360:28-39
  • 58. Gawron K, Jensen DA, Steplewski A, Fertala A: Reducing the effects of intracellular accumulation of
  • thermolabile collagen II mutants by increasing their thermostability in cell culture conditions, Biochem
  • Biophys
  • Res Commun 2010, 396:213-218
  • 59. Mahoney MG, Sadowski S, Brennan D, Pikander P, Saukko P, Wahl J, Aho H, Heikinheimo K,
  • Bruckner-Tuderman L, Fertala A, Peltonen J, Uitto J, Peltonen S: Compound heterozygous desmoplakin
  • mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities, J
  • Invest Dermatol 2010, 130:968-978
  • 60. Zhang RZ, Zou Y, Pan TC, Markova D, Fertala A, Hu Y, Squarzoni S, Reed UC, Marie SK, Bonnemann
  • CG, Chu ML: COL6A2 recessive C-globular missense mutations in ullrich congenital muscular dystrophy:
  • Role
  • of the C2A splice variant, J Biol Chem 2010,
  • 61. Zhang RZ, Zou Y, Pan TC, Markova D, Fertala A, Hu Y, Squarzoni S, Reed UC, Marie SK, Bonnemann
  • CG, Chu ML: Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy:
  • role of the C2a splice variant, J Biol Chem 2010, 285:10005-10015
  • 62. Jensen DA, Steplewski A, Gawron K, Fertala A: Persistence of intracellular and extracellular changes
  • after incompletely suppressing expression of the R789C (p.R989C) and R992C (p.R1192C) collagen II
  • mutants,
  • Hum Mutat 2011, 32:794-805
  • 63. Lee B, Clarke D, Al Ahmad A, Kahle M, Parham C, Auckland L, Shaw C, Fidanboylu M, Orr AW,
  • Ogunshola O, Fertala A, Thomas SA, Bix GJ: Perlecan domain V is neuroprotective and proangiogenic
  • following ischemic stroke in rodents, J Clin Invest 2011, 121:3005-3023
  • 64. Clarke DN, Al Ahmad A, Lee B, Parham C, Auckland L, Fertala A, Kahle M, Shaw CS, Roberts J, Bix
  • GJ: Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin alpha5beta1 and
  • ERK-dependent signaling pathways, PLoS One 2012, 7:e45257
  • 65. Denning D, Abu-Rub MT, Zeugolis DI, Habelitz S, Pandit A, Fertala A, Rodriguez BJ:
  • Electromechanical
  • properties of dried tendon and isoelectrically focused collagen hydrogels, Acta biomaterialia 2012, 8:3073-
  • 3079
  • 66. Denning D, Alilat S, Habelitz S, Fertala A, Rodriguez BJ: Visualizing molecular polar order in tissues
  • via
  • electromechanical coupling, Journal of structural biology 2012, 180:409-419
  • 67. Steplewski A, Fertala A: Inhibition of collagen fibril formation, Fibrogenesis Tissue Repair 2012, 5 Suppl
  • 1:S29
  • 68. Steplewski A, Kasinskas A, Fertala A: Remodeling of the dermal-epidermal junction in bilayered skin
  • constructs after silencing the expression of the p.R2622Q and p.G2623C collagen VII mutants, Connect
  • Tissue Res 2012, 53:379-389
  • 69. Arnold WV, Fertala A: Skeletal diseases caused by mutations that affect collagen structure and
  • function,
  • Int J Biochem Cell Biol 2013, 45:1556-1567
  • 70. Barnes AM, Duncan G, Weis M, Paton W, Cabral WA, Mertz EL, Makareeva E, Gambello MJ,
  • Lacbawan FL, Leikin S, Fertala A, Eyre DR, Bale SJ, Marini JC: Kuskokwim Syndrome, a Recessive
  • Congenital Contracture Disorder, Extends the Phenotype of FKBP10 Mutations, Hum Mutat 2013, 34:1279-
  • 1288
  • 71. Fertala J, Steplewski A, Kostas J, Beredjiklian P, Williams G, Arnold W, Abboud J, Bhardwaj A, Hou
  • C,
  • Fertala A: Engineering and characterization of the chimeric antibody that targets the C-terminal telopeptide of
  • the alpha2 chain of human collagen I: a next step in the quest to reduce localized fibrosis, Connect Tissue
  • Res 2013, 54:187-196
  • 72. Fertala J, Kostas J, Hou C, Steplewski A, Beredjiklian P, Abboud J, Arnold WV, Williams G, Fertala A:
  • Testing the anti-fibrotic potential of the single-chain Fv antibody against the alpha2 C-terminal telopeptide of
  • collagen I, Connect Tissue Res 2014, 55:115-122
COS Profile

Last Updated by Andrzej Fertala, PhD: Thursday, October 13, 2011 5:32:01 PM

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