Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

in Journal of Endocrinology
Correspondence should be addressed to T Wells: wellst@cardiff.ac.uk
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Human Prader–Willi syndrome (PWS) is characterised by impairments of multiple systems including the growth hormone (GH) axis and skeletal growth. To address our lack of knowledge of the influence of PWS on skeletal integrity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-ICdel mouse model for ‘full’ PWS and determined the impact of thermoneutrality. Tibial length, epiphyseal plate width and marrow adiposity were reduced by 6, 18 and 79% in male PWS-ICdel mice, with osteoclast density being unaffected. Similar reductions in femoral length accompanied a 32% reduction in mid-diaphyseal cortical diameter. Distal femoral Tb.N was reduced by 62%, with individual trabeculae being less plate-like and the lattice being more fragmented (Tb.Pf increased by 63%). Cortical strength (ultimate moment) was reduced by 26% as a result of reductions in calcified tissue strength and the geometric contribution. GH and prolactin contents in PWS-ICdel pituitaries were reduced in proportion to their smaller pituitary size, with circulating IGF-1 concentration reduced by 37–47%. Conversely, while pituitary luteinising hormone content was halved, circulating gonadotropin concentrations were unaffected. Although longitudinal growth, marrow adiposity and femoral geometry were unaffected by thermoneutrality, strengthened calcified tissue reversed the weakened cortex of PWS-ICdel femora. While underactivity of the GH axis may be due to loss of Snord116 expression and impaired limb bone geometry and strength due to loss of Magel2 expression, comprehensive analysis of skeletal integrity in the single gene deletion models is required. Our data imply that thermoneutrality may ameliorate the elevated fracture risk associated with PWS.

 

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    PWS-ICdel mice show impaired tibial growth and adiposity. (A) Quantification of tibial length in 18-month-old male WT and PWS-ICdel littermate mice. Tibial epiphysial plate (EP) width (B) was quantified in Masson’s Trichrome-stained sections and tibial marrow adiposity (C), marrow adipocyte number (D), size (E) and size profile (F) quantified in digital images of Toluidene blue-stained sections from WT (a) and PWS-ICdel (b) littermates. Osteoclast density (G) was quantified in TRAP+-stained sections. Data shown are mean ± s.e.m. (n = 6 for both genotypes), with statistical comparisons performed by Student’s unpaired t-test (*P < 0.05; **P < 0.01; ***P < 0.001 vs WT littermates).

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    PWS-ICdel mice show impaired femoral morphology. Measurement of femoral length (A), outer cortical (anterior-posterior) diameter (A-P Ø; B) and average cortical wall thickness (C) in 18-month-old male WT (n = 6 (3 for B and C)) and PWS-ICdel (n = 6) littermate mice. µ-CT was used to quantify the number (Tb.N; D), thickness (Tb.Th; E), cross-sectional shape (structural modal (SM) index; F), relative surface (BS/BV; G), separation (Tb.Sp; H) and lattice fragmentation (Pattern factor; I) of trabeculae in the distal femora. Data shown are mean ± s.e.m., with statistical comparisons performed by Student’s unpaired t-test (*P < 0.05; **P < 0.01 vs WT littermates).

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    PWS-ICdel mice show compromised femoral strength. Measurement of femoral strength (ultimate moment; A), tissue strength (ultimate tensile stress; B) and the geometric contribution to strength (second moment of area; C) in 18-month-old male WT (n = 6 (3 for B and C)) and PWS-ICdel (n = 6) littermate mice. Data shown are mean ± s.e.m., with statistical comparisons performed by Student’s unpaired t-test (*P < 0.05 vs WT littermates).

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    PWS-ICdel mice show multiple pituitary hormone deficiencies. Quantification of pituitary weight (A) and growth hormone (GH; B), prolactin (PRL; C) and luteinising hormone (LH; D) contents in 6–15-month-old male and female WT (n = 6) and PWS-ICdel (n = 6 (male) and 5 (female)) littermate mice. Data shown are mean ± s.e.m., with statistical comparisons performed by 1-way ANOVA and Bonferroni post hoc test (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs WT littermates (same sex); †† P < 0.01; †††† P < 0.0001 vs male littermates (same genotype)).

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    PWS-ICdel mice show reduced GH-IGF-1 axis activity. Quantification of pituitary weight (A) and plasma insulin-like growth factor-1 (IGF-1; B), luteinising hormone (LH; C) and follicle-stimulating hormone (FSH; D) in 5–9-month-old male and female WT and PWS-ICdel (n = 6 per group) littermate mice. Data shown are mean ± s.e.m., with statistical comparisons performed by 1-way ANOVA and Bonferroni post hoc test (A and B) or Kruskal–Wallis test (C and D) (***P < 0.001; ****P < 0.0001 vs WT littermates (same sex); †††† P < 0.0001 vs male littermates (same genotype)).

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    Thermoneutrality has little effect on growth and marrow adiposity in PWS-ICdel mice. Tibial length (A), epiphyseal plate (EP) width (B), marrow adiposity (C), marrow adipocyte number (D) and mean adipocyte size (E) were quantified in 6–15-month-old male WT and PWS-ICdel littermate mice after being maintained at either standard ambient temperature (20–22°C) or thermoneutrality (30°C) for 9 weeks. Adipocyte size profiles are presented for standard ambient temperature (F) and thermoneutrality (G). Data shown are mean ± s.e.m. (n = 6 (room temperature) and 5 (thermoneutrality)), with statistical comparisons performed by 1-way ANOVA and Bonferroni post hoc test (A–E; ****P < 0.0001 vs room temperature (same genotype)) or unpaired Student’s t-test (F and G; *P < 0.05 vs WT littermates (same temperature)).

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    Thermoneutrality alleviates impaired femoral strength in PWS-ICdel mice. Femoral length (A), cortical anterior-posterior diameter (A-P Ø; B), average cortical wall thickness (C), cortical strength (ultimate moment; D), tissue strength (ultimate tensile stress; E) and the geometric contribution to strength (second moment of area; F) were quantified in 6–15-month-old male WT and PWS-ICdel after being maintained at either standard ambient temperature (20–22°C) or thermoneutrality (30°C) for 9 weeks (n = 6 (room temperature) and 5 (thermoneutrality)). Data shown are mean ± s.e.m., with statistical comparisons performed by 1-way ANOVA and Bonferroni post hoc test (**P < 0.01; ****P < 0.0001 vs WT littermates (same ambient temperature)).

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