Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development.
BACKGROUND
Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD).


RESULTS
Two hundred and eighty-four consecutive neonates with a gestational age of <28 weeks were included in this prospective study. Forty-five neonates developed BPD. Nine single-nucleotide polymorphisms (SNPs) were sought in the MMP2, MMP14 and MMP16 genes. After adjustment for birth weight and ethnic origin, the TT genotype of MMP16 C/T (rs2664352) and the GG genotype of MMP16 A/G (rs2664349) were found to protect from BPD. These genotypes were also associated with a smaller active fraction of MMP2 and with a 3-fold-lower MMP16 protein level in tracheal aspirates collected within 3 days after birth. Further evaluation of MMP16 expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage. In two newborn rat models of arrested alveolarization the lung MMP16 mRNA level was less than 50% of normal.


CONCLUSIONS
MMP16 may be involved in the development of lung alveoli. MMP16 polymorphisms appear to influence not only the pulmonary expression and function of MMP16 but also the risk of BPD in premature infants.
Hadchouel
Alice
A
INSERM, Unité 841, IMRB, équipe 06, Créteil, France.
Decobert
Fabrice
F
Franco-Montoya
Marie-Laure
ML
Halphen
Isabelle
I
Jarreau
Pierre-Henri
PH
Boucherat
Olivier
O
Martin
Emmanuel
E
Benachi
Alexandra
A
Amselem
Serge
S
Bourbon
Jacques
J
Danan
Claude
C
Delacourt
Christophe
C
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008168:Lung / Q000201:enzymology* / Q000254:growth & development*; D008297:Male; D053513:Matrix Metalloproteinase 16 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000494:pharmacology; D014132:Trachea / Q000201:enzymology / Q000254:growth & development
D013501:Surface-Active Agents; D053513:Matrix Metalloproteinase 16
Dev Dyn. 2005 Apr;232(4):1079-90
15739229
J Biol Chem. 2003 Oct 3;278(40):38765-71
12878590
Am J Respir Crit Care Med. 2007 May 15;175(10):1066-77
17303798
Hum Mol Genet. 2004 Jun 1;13(11):1095-104
15102713
Pediatr Res. 2004 May;55(5):794-801
14973177
Sarcoidosis Vasc Diffuse Lung Dis. 2006 Mar;23(1):13-21
16933466
PLoS Med. 2007 Jul 31;4(7):e237
17676984
Pediatrics. 2004 Aug;114(2):e243-8
15286263
Am J Respir Crit Care Med. 2002 May 15;165(10):1384-7
12016100
Am J Physiol Lung Cell Mol Physiol. 2002 Nov;283(5):L1086-93
12376362
Am J Physiol Lung Cell Mol Physiol. 2002 Oct;283(4):L747-54
12225951
Int J Mol Med. 2006 Apr;17(4):621-6
16525718
Dev Biol. 2005 Jan 1;277(1):255-69
15572153
Pediatr Res. 2007 Jul;62(1):20-5
17515830
Annu Rev Physiol. 1984;46:617-28
6370120
Physiol Rev. 2007 Jan;87(1):69-98
17237343
J Biol Chem. 1995 Sep 29;270(39):23013-20
7559440
Carcinogenesis. 2005 Jun;26(6):1117-21
15731163
Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9
11401896
Pediatrics. 2004 Nov;114(5):1305-11
15520112
Biochim Biophys Acta. 1997 Nov 1;1354(2):159-70
9396633
J Cell Sci. 2002 Feb 15;115(Pt 4):839-48
11865039
Dev Biol. 2008 Jan 1;313(1):196-209
18022611
Cancer Res. 2002 Nov 15;62(22):6430-3
12438229
J Biol Chem. 2001 Mar 9;276(10):7549-58
11114309
Pediatrics. 2006 Jun;117(6):1901-6
16740829
J Perinatol. 2004 Jan;24(1):30-5
14726935
Physiol Genomics. 2007 Dec 19;32(1):128-41
17911382
J Biol Chem. 2004 Mar 5;279(10):8592-601
14681236
Int J Dev Biol. 2007;51(5):389-95
17616928
Am J Obstet Gynecol. 2007 Feb;196(2):147.e1-8
17306659