Background: Mice carrying mutations in DNA repair genes often show signs of accelerated ageing and therefore can be used as a model system to study age related diseases like osteoporosis. It has been shown that TTD mice, carrying a mutation in the nucleotide excision repair gene XPD (xeroderma pigmentosa group D), display features of ageing related osteoporosis as well as adipose tissue hypoplasia. Since both cell types involved, osteoblasts as well as adipocytes, arise from the same mesenchymal stem cell population, the aim of the current project was to study the number, proliferation and differentiation potential of these cells in TTD compared to wild type (WT) mice. This might provide us with useful information concerning the mechanism behind age-related osteoporosis and the loss of adipose tissue.Methods: Bone marrow from old TTD and WT mice was cultured under osteogenic or adipogenic conditions and analysed for alkaline phosphatase activity (ALP), mineralisation (osteoblast) and lipid deposition (adipocyte).Results: Under osteogenic conditions the number of ALP-positive colonies after 9 and 14 days of culture was significantly decreased (p=0.02) in TTD compared to WT mice. The rate at which new ALP-positive colonies are formed between day 9 and day 14 of culture has not changed between TTD and WT mice, indicating that the decrease in colony number is not due to a delay in differentiation. Mineralisation of ALP-positive colonies did not seem to be affected, with a borderline significant decrease on day 14 at the onset of mineralisation but no significant changes on day 21 of culture. Lipid deposition was strongly reduced in TTD compared to WT mice (p=0.01) after 35 days of culture.Conclusions: The observed reduction in osteoblast and adipocyte differentiation indicates a reduction of mesenchymal stem cell numbers in TTD mice. This reduction in mesenchymal stem cell numbers and the corresponding decline in osteoblast differentiation could explain the premature osteoporotic features observed in TTD mice. In line with this, the reduction of mesenchymal stem cells and adipocyte differentiation may underlie the adipose tissue hypoplasia observed in TTD mice
