title: Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression.
abstract: Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc(tm1cam) exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc(tm1cam) null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc(tm1cam) null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc(tm1cam) cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis.
authors: School of Biosciences, Cardiff University, Cardiff. manserghf@tcd.ie
authors: Fiona C
authors: FC
authors: Mansergh
authors: Timothy
authors: T
authors: Wells
authors: Carole
authors: C
authors: Elford
authors: Samuel L
authors: SL
authors: Evans
authors: Mark J
authors: MJ
authors: Perry
authors: Martin J
authors: MJ
authors: Evans
authors: Bronwen A J
authors: BA
authors: Evans
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics*; D001854:Bone Marrow Cells / Q000166:cytology; D019245:Compressive Strength; D004195:Disease Models, Animal; D005091:Exons; D005269:Femur / Q000502:physiology*; D005786:Gene Expression Regulation; D020738:Leptin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D015676:Osteonectin / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype
chemical_list: D020738:Leptin; D015676:Osteonectin