Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia.
ADAMTS Proteins
/ genetics
Animals
Animals, Newborn
Bone Diseases, Developmental
/ genetics
Disease Models, Animal
Extremities
/ growth & development
Fibrillin-1
/ metabolism
Fibrillin-2
/ metabolism
Fibrillins
/ metabolism
Gene Deletion
Gene Expression Regulation, Developmental
Humans
Limb Deformities, Congenital
/ genetics
Mice
Organ Specificity
Tendons
/ growth & development
ADAMTS-like protein
Acromelic dysplasia
Fibrillin microfibrils
Geleophysic dysplasia
Skeletal growth
Tendon
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
07
09
2018
revised:
01
02
2019
accepted:
06
02
2019
pubmed:
11
2
2019
medline:
6
5
2020
entrez:
11
2
2019
Statut:
ppublish
Résumé
Geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature with progressive joint contractures, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and fibrillin microfibrils. Mice lacking ADAMTSL2 die at birth, which has precluded analysis of postnatal limb development and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. Here, detailed expression analysis of Adamtsl2 using an intragenic lacZ reporter shows strong Adamtsl2 expression in limb tendons. Expression in developing and growing bones is present in regions that are destined to become articular cartilage but is absent in growth plate cartilage. Consistent with strong tendon expression, Adamtsl2 conditional deletion in limb mesenchyme using Prx1-Cre led to tendon anomalies, albeit with normal collagen fibrils, and distal limb shortening, providing a mouse model for geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx-Cre, a tendon-specific Cre-deleter strain, which does not delete in cartilage, also impaired skeletal growth. Recombinant ADAMTSL2 is shown here to colocalize with fibrillin microfibrils in vitro, and enhanced staining of fibrillin-1 microfibrils was observed in Prx1-Cre Adamtsl2 tendons. The findings show that ADAMTSL2 specifically regulates microfibril assembly in tendons and that proper microfibril composition in tendons is necessary for tendon growth. We speculate that reduced bone growth in geleophysic dysplasia may result from external tethering by short tendons rather than intrinsic growth plate anomalies. Taken together with previous work, we suggest that GD results from abnormal microfibril assembly in tissues, and that ADAMTSL2 may limit the assembly of fibrillin microfibrils.
Identifiants
pubmed: 30738849
pii: S0945-053X(18)30372-X
doi: 10.1016/j.matbio.2019.02.001
pmc: PMC6685762
mid: NIHMS1521930
pii:
doi:
Substances chimiques
Fbn1 protein, mouse
0
Fbn2 protein, mouse
0
Fibrillin-1
0
Fibrillin-2
0
Fibrillins
0
ADAMTS Proteins
EC 3.4.24.-
ADAMTSL2 protein, human
EC 3.4.24.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
38-53Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR044745
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR053890
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR070748
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR026820
Pays : United States
Informations de copyright
Copyright © 2019 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
Références
Am J Med Genet. 1997 Oct 3;72(1):85-90
pubmed: 9295082
J Biol Chem. 2009 Nov 13;284(46):31493-7
pubmed: 19734141
Am J Phys Anthropol. 2004;Suppl 39:63-99
pubmed: 15605390
FEBS J. 2013 May;280(10):2120-37
pubmed: 23331954
Pediatr Endocrinol Rev. 2009 Mar;6(3):418-23
pubmed: 19396027
J Cell Biol. 1997 Feb 10;136(3):729-43
pubmed: 9024701
Sci Rep. 2017 Feb 08;7:41871
pubmed: 28176809
Mol Biol Cell. 2009 Feb;20(3):846-58
pubmed: 19037100
J Biol Chem. 2002 Dec 27;277(52):50795-804
pubmed: 12399449
Matrix Biol. 2018 Oct;71-72:225-239
pubmed: 29885460
FASEB J. 2002 May;16(7):673-80
pubmed: 11978731
J Biol Chem. 2011 Feb 18;286(7):5087-99
pubmed: 21135108
Ann Trop Paediatr. 2008 Jun;28(2):161-4
pubmed: 18510828
PLoS One. 2012;7(8):e42522
pubmed: 22905142
Matrix Biol. 2015 May-Jul;44-46:24-37
pubmed: 25770910
Am J Hum Genet. 2011 Jul 15;89(1):7-14
pubmed: 21683322
Hum Mol Genet. 2015 Aug 1;24(15):4454-63
pubmed: 25979247
J Vet Intern Med. 2017 Mar;31(2):532-538
pubmed: 28158899
Am J Med Genet. 1996 May 3;63(1):50-4
pubmed: 8723086
Am J Hum Genet. 2004 Nov;75(5):801-6
pubmed: 15368195
PLoS One. 2012;7(11):e48634
pubmed: 23133647
FASEB J. 2019 Feb;33(2):2707-2718
pubmed: 30303737
Development. 1998 Mar;125(6):1067-73
pubmed: 9463353
Invest Ophthalmol Vis Sci. 2013 Dec 23;54(13):8337-44
pubmed: 24265020
J Biol Chem. 2008 Sep 12;283(37):25533-43
pubmed: 18625713
Ann Pediatr Endocrinol Metab. 2015 Mar;20(1):8-12
pubmed: 25883921
Nat Genet. 1995 Dec;11(4):456-8
pubmed: 7493032
Am J Med Genet A. 2013 Sep;161A(9):2305-10
pubmed: 23897642
Matrix Biol. 2018 Oct;71-72:82-89
pubmed: 28782645
Am J Hum Genet. 2009 Nov;85(5):558-68
pubmed: 19836009
Genesis. 2002 Jun;33(2):77-80
pubmed: 12112875
J Biol Chem. 1999 Apr 2;274(14):9636-47
pubmed: 10092650
Dev Cell. 2009 Nov;17(5):687-98
pubmed: 19922873
Semin Cell Dev Biol. 2017 Feb;62:16-33
pubmed: 27180955
J Biol Chem. 2011 May 13;286(19):17156-67
pubmed: 21402694
Matrix Biol. 2007 Jul;26(6):431-41
pubmed: 17509843
J Cell Biochem. 2012 Feb;113(2):410-8
pubmed: 22223425
Nat Genet. 2008 Sep;40(9):1119-23
pubmed: 18677313
J Med Genet. 2003 Jan;40(1):34-6
pubmed: 12525539
Matrix Biol. 1996 Sep;15(4):231-8
pubmed: 8892223
Structure. 2003 Sep;11(9):1179-88
pubmed: 12962636
Matrix Biol. 2011 Jan;30(1):43-52
pubmed: 20970500
Matrix Biol. 2019 Jul;80:6-13
pubmed: 30219651
Dis Model Mech. 2015 May;8(5):487-99
pubmed: 25762570
J Cell Biol. 1995 May;129(4):1165-76
pubmed: 7744963
Dev Dyn. 2002 Nov;225(3):250-9
pubmed: 12412007
J Med Genet. 2011 Jun;48(6):417-21
pubmed: 21415077
J Biol Chem. 2001 Sep 21;276(38):36035-42
pubmed: 11461921
J Mol Endocrinol. 2014 Aug;53(1):T1-9
pubmed: 24740736
J Obstet Gynaecol. 2005 Nov;25(8):818-20
pubmed: 16368598
J Pediatr. 1990 Aug;117(2 Pt 1):227-32
pubmed: 2380821
Dev Cell. 2009 Dec;17(6):861-73
pubmed: 20059955
Int J Biochem Cell Biol. 2004 Jun;36(6):1079-84
pubmed: 15094122
Connect Tissue Res. 1995;31(2):87-97
pubmed: 15612324
Matrix Biol. 2019 Apr;77:117-128
pubmed: 30201140
Hum Mutat. 2009 Mar;30(3):334-41
pubmed: 19006240
Clin Genet. 2009 Sep;76(3):276-81
pubmed: 19664000
PLoS One. 2010 Sep 17;5(9):
pubmed: 20862248
Matrix Biol. 2015 Sep;47:34-43
pubmed: 25957949
J Biol Chem. 2008 May 16;283(20):13874-88
pubmed: 18339631
Hum Mutat. 2008 Dec;29(12):1425-34
pubmed: 18567016