title: Secreted phosphoprotein 1 is a determinant of lung function development in mice.
abstract: Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1((-/-)) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (Lm) compared with Spp1((+/+)) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, wingless-related mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1((-/-)) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased Lm). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1((-/-)) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.
authors.affiliation: 1 Department of Environmental and Occupational Health, Graduate School of Public Health.
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Martin
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Concel
authors.forename: Swapna
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Kiflai
authors.initials: K
authors.lastname: Bein
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brant
authors.forename: Leema
authors.initials: L
authors.lastname: George
authors.forename: Ankita
authors.initials: A
authors.lastname: Mitra
authors.forename: Tania A
authors.initials: TA
authors.lastname: Thimraj
authors.forename: James P
authors.initials: JP
authors.lastname: Fabisiak
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Vuga
authors.forename: Cheryl
authors.initials: C
authors.lastname: Fattman
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
mesh_terms: D056809:Alveolar Epithelial Cells / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008170:Lung Compliance / Q000235:genetics; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology / Q000254:growth & development* / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C493716:Runx2 protein, mouse; C506896:Spp1 protein, mouse; D053495:Osteopontin
keywords: asthma; chronic obstructive pulmonary disease; emphysema; osteopontin; pulmonary fibrosis