Thermoneutrality improves skeletal impairment in adult Prader-Willi syndrome mice

Human Prader-Willi syndrome (PWS) is characterised by impairmen ts of multiple systems including the growth hormone (GH) axis and skeletal gro wth. To address our lack of knowledge of the influence of PWS on skeletal integr ity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-I Cdel 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 reductio ns 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 str ength 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 thermoneutrali ty, strengthened calcified tissue reversed the weakened cortex of PWS-IC del 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 requir ed. Our data imply that thermoneutrality may ameliorate the elevated fracture risk asso ciated with PWS.