Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor β-receptor 1 and 2 (TGFβ-R1 and TGFβ-R2) genes. Fibroblasts derived from 12 Loeys-Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT-PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFβ-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFβ-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1- and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFβ-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFβ-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome.
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Christopher P
CP
Barnett
David
D
Chitayat
Timothy J
TJ
Bradley
Yanting
Y
Wang
Aleksander
A
Hinek
D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D018929:Cell Culture Techniques; D003094:Collagen / Q000096:biosynthesis* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004547:Elastic Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004549:Elastin / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005260:Female; D005333:Fetus; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D055947:Loeys-Dietz Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008840:Microfilament Proteins / Q000096:biosynthesis; D008854:Microscopy, Electron; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014333:Tropoelastin / Q000096:biosynthesis; D054392:Adipokines
D002135:Calcium-Binding Proteins; D003094:Collagen; D003907:Dexamethasone; D004549:Elastin; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D014333:Tropoelastin; C403672:EFEMP2 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C060820:fibulin
Expert Rev Mol Med. 2006 Aug 08;8(19):1-23
16893474
J Cell Sci. 1999 Nov;112 ( Pt 22):4163-71
10547375
J Periodontal Res. 2002 Jun;37(3):196-203
12113554
Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L944-52
17209135
Am J Surg Pathol. 2009 Feb;33(2):194-201
18852674
Lab Invest. 1981 Apr;44(4):342-50
7193778
Nat Clin Pract Endocrinol Metab. 2007 May;3(5):405-13
17452967
J Invest Dermatol. 1994 Nov;103(5):632-6
7963646
J Occup Environ Med. 2000 Jun;42(6):582-7
10874650
Nat Genet. 2005 Mar;37(3):275-81
15731757
Clin Genet. 2008 Mar;73(3):290-3
18070134
Am J Physiol. 1999 Dec;277(6):L1205-13
10600892
Eur J Biochem. 1998 Nov 15;258(1):1-18
9851686
FASEB J. 1995 May;9(8):576-96
7768349
N Engl J Med. 2006 Aug 24;355(8):788-98
16928994
J Cell Sci. 1999 Apr;112 ( Pt 7):1093-100
10198291
Exp Toxicol Pathol. 2003 Nov;55(4):257-64
14703771
Nat Genet. 2003 Mar;33(3):407-11
12598898
J Clin Invest. 2004 Dec;114(11):1586-92
15546004
Nature. 1994 Aug 4;370(6488):341-7
8047140
J Appl Physiol (1985). 2005 Mar;98(3):881-8
15465892
Invest Ophthalmol Vis Sci. 2002 Dec;43(12):3691-7
12454038
Am J Hum Genet. 2002 Jul;71(1):30-44
12016585
Science. 2006 Apr 7;312(5770):117-21
16601194
Clin Genet. 2005 Dec;68(6):561-3
16283890
J Biol Chem. 2003 Jan 24;278(4):2750-7
12429738
N Engl J Med. 2008 Jun 26;358(26):2787-95
18579813
N Engl J Med. 2007 Sep 20;357(12):1179-89
17881750
Prenat Diagn. 2006 Nov;26(11):1081-3
16981219
Am J Respir Cell Mol Biol. 1994 Dec;11(6):751-5
7946403
Hum Mutat. 2006 Aug;27(8):770-7
16799921