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Fibroblast Growth Factor Receptor Signaling Regulates Extracellular Matrix Gene Expression during Alveogenesis

Division of Pulmonary Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, Texas

Correspondence and requests for reprints should be addressed to Thomas J. Mariani, Ph.D., Pulmonary Medicine Thorn 8, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115. E-mail: tmariani{at}partners.org

The molecular mechanisms controlling lung maturation are relevant to a complete understanding of chronic obstructive pulmonary disease due to their potential role in the disease process and therapeutic potential as targets for promoting tissue repair. Analysis of expression profiling data describing normal lung development revealed that FGFR3 and FGFR4 co-cluster with a group of extracellular matrix (ECM) genes with prominent expression during alveogenesis. Previous investigation has demonstrated a specific failure of alveogenesis in mice bearing compound mutations of fibroblast growth factor receptor 3 (FGFR3) and FGFR4, indicating that these receptors cooperatively promote postnatal alveolar formation. Recapitulation and analysis of compound FGFR3/4 deficiency in a pure C57BL/6 background reveal severe defects in lung maturation, including significant airspace enlargement in the absence of septation, beginning at Postnatal Day 7. We sought to further define the contribution of FGF signaling to the regulation of airspace ECM composition in an effort to elucidate the mechanisms leading to this phenotype. Genomewide expression profiling of lung tissue at 4 wk of age revealed co-clustering of wild-type and compound heterozygote samples, and a separate cluster for compound mutants, indicating differences in genomic profiles consistent with the observed morphologic differences. Statistical analysis of microarray data identified 14 up-regulated genes and 15 down-regulated genes in compound mutants relative to the wild-type and compound heterozygote lungs. Quantitative real-time polymerase chain reaction validated significant (p < 0.01) increases in the expression of several ECM genes, including biglycan (5.9-fold), lysyl oxidase-like 1/loxl1 (4.8-fold), elastin (10.9-fold), fibrillin (2.9-fold), microfibrillar-associated protein 5/MAGP2 (2.0-fold), asporin (4.9-fold), and SerpinE2 (6.6-fold), in the lungs of compound mutants (n = 9), compared with wild-type (n = 9) and compound heterozygote mice (n = 12). Biochemical analysis confirmed that the increase in elastin fiber gene expression is accompanied by increased deposition of mature elastin fibers. Interestingly, histochemical analysis of elastin within mutant lungs revealed excess fibers distributed throughout the alveolar wall, not restricted to defined locations as is observed in wild-type animals. In vitro studies further showed that ECM genes are targets of FGF signaling in lung cells. In particular, the FGFR3/4 ligands FGF1 and FGF2 were found to repress loxl1 gene expression in both primary mouse lung fibroblasts and in the MLE-15 mouse lung alveolar epithelial cell line. Furthermore, FGF1 and FGF2 were found to induce the expression of matrix -carboxyglutamic acid protein (MGP) in MLE-15 cells and repress expression of type IV collagen and osteonectin in primary lung fibroblasts. This study begins to define the FGFR3/FGFR4-dependent mechanisms of alveolar formation during postnatal lung development and supports the hypothesis that FGFR signaling contributes to lung maturation through regulation of ECM gene expression.

FOOTNOTES

Supported by National Institutes of Health grant HL71885 (T.J.M.).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 16, 2006; accepted in final form April 4, 2006)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Srisuma, S. Articles by Mariani, T. J. Search for Related Content PubMed Articles by Srisuma, S. Articles by Mariani, T. J.