Secreted phosphoprotein 1 is a determinant of lung function development in mice

Am J Respir Cell Mol Biol. 2014 Nov;51(5):637-51. doi: 10.1165/rcmb.2013-0471OC.

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.

Keywords: asthma; chronic obstructive pulmonary disease; emphysema; osteopontin; pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / physiology
  • Animals
  • Animals, Newborn
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Female
  • Gene Expression Regulation, Developmental*
  • Lung Compliance / genetics
  • Male
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Osteopontin / genetics*
  • Promoter Regions, Genetic / genetics
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / growth & development*
  • Pulmonary Alveoli / physiology*
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Receptor, Notch1 / genetics

Substances

  • Core Binding Factor Alpha 1 Subunit
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Runx2 protein, mouse
  • Spp1 protein, mouse
  • Osteopontin