title: ADAMTS4 and ADAMTS5 knockout mice are protected from versican but not aggrecan or brevican proteolysis during spinal cord injury.
abstract: The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.
authors.affiliation: Department of Medical Biology, Turgut Ozal University School of Medicine, 06200 Ankara, Turkey.
authors.forename: Kadir
authors.initials: K
authors.lastname: Demircan
authors.affiliation: Department of Medical Genetics, Zekai Tahir Burak Women's Health Training and Research Hospital, 06230 Ankara, Turkey.
authors.forename: Vehap
authors.initials: V
authors.lastname: Topcu
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takigawa
authors.affiliation: Vocational School of Health Sciences, Turgut Ozal University, 06374 Ankara, Turkey ; Department of Biochemistry, Gaziosmanpasa University School of Medicine, 60000 Tokat, Turkey.
authors.forename: Sumeyya
authors.initials: S
authors.lastname: Akyol
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yonezawa
authors.affiliation: Department of Clinical Biochemistry, Diskapi Yildirim Beyazit Training and Research Hospital, 06200 Ankara, Turkey.
authors.forename: Gulfer
authors.initials: G
authors.lastname: Ozturk
authors.affiliation: Private Bilecik Orhangazi Dialysis Center, 11000 Bilecik, Turkey.
authors.forename: Veli
authors.initials: V
authors.lastname: Ugurcu
authors.affiliation: Vocational School of Health Sciences, Turgut Ozal University, 06374 Ankara, Turkey ; Department of Biochemistry, Gaziosmanpasa University School of Medicine, 60000 Tokat, Turkey.
authors.forename: Rukiye
authors.initials: R
authors.lastname: Hasgul
authors.affiliation: Department of Biochemistry, Turgut Ozal University School of Medicine, 06200 Ankara, Turkey.
authors.forename: M Ramazan
authors.initials: MR
authors.lastname: Yigitoglu
authors.affiliation: Department of Biochemistry, Hacettepe University Medical Faculty, 06200 Ankara, Turkey.
authors.forename: Omer
authors.identifier: 0000-0001-5496-9392
authors.initials: O
authors.lastname: Akyol
authors.affiliation: School of Medicine, Faculty of Health, Deakin University, 75 Pigdons Road, Waurn Ponds, VIC 3216, Australia ; Molecular and Medical Research SRC, Deakin University, 75 Pigdons Road,Waurn Ponds, VIC 3216, Australia.
authors.forename: Daniel R
authors.identifier: 0000-0003-0269-5857
authors.initials: DR
authors.lastname: McCulloch
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0002-4815-5891
authors.initials: S
authors.lastname: Hirohata
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D058581:Brevican / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology; D053675:Versicans / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D058581:Brevican; D053675:Versicans; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse
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