Age-related bone loss in the LOU/c rat model of healthy ageing Gustavo Duque a,b, * , Daniel Rivas b , Wei Li a,c , Ailian Li c , Janet E. Henderson c , Guylaine Ferland d , Pierrette Gaudreau e a Aging Bone Research Program, Nepean Clinical School, University of Sydney, Level 5, South Block, Nepean Hospital, Penrith, NSW 2750, Australia b Lady Davis Institute for Medical Research, McGill University, Montreal, Que., Canada H3T 1E2 c Department of Medicine, JTN Wong Laboratories for Mineralized Tissue Research, McGill University Health Centre, Montreal, Que., Canada H3G 1Y6 d Institut Universitaire de Gériatrie de Montréal, Montreal, Que., Canada H3W 1W5 e Laboratory of Neuroendocrinology of aging, Centre hospitalier de l’Université de Montréal Research Center (CRCHUM), Montreal, Que., Canada H1W 4A4 article info Article history: Received 5 June 2008 Received in revised form 8 October 2008 Accepted 10 October 2008 Available online 21 October 2008 Keywords: Aging Osteoporosis Animal models Osteoblasts Adipocytes Bone turnover abstract Inbred albino Louvain (LOU) rats are considered a model of healthy aging due to their increased longevity in the absence of obesity and with a low incidence of common age-related diseases. In this study, we characterized the bone phenotype of male and female LOU rats at 4, 20 and 27 months of age using quan- titative micro computed tomographic (mCT) imaging, histology and biochemical analysis of circulating bone biomarkers. Bone quality and morphometry of the distal femora, assessed by mCT, was similar in male and female rats at 4 months of age and deteriorated over time. Histochemical staining of undecal- cified bone showed a significant reduction in cortical and trabecular bone by 20 months of age. The reduction in mineralized tissue was accompanied by reduced numbers of osteoblasts and osteoclasts and a significant increase in marrow adiposity. Biochemical markers of bone turnover, C-telopeptide and osteocalcin, correlated with the age-related bone loss whereas the calciotropic hormones PTH and vitamin D remained unchanged over time. In summary, aged LOU rats exhibit low-turnover bone loss and marrow fat infiltration, which are the hallmarks of senile osteoporosis, and thus represent a novel model in which to study the molecular mechanisms leading to this disorder. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction Age-related bone loss is the primary underlying cause of frac- tures in older persons (Raisz, 2005). Cellular changes in the ageing skeleton include an increased rate of adipogenesis at the expense of a reduction in osteoblastogenesis (Duque and Troen, 2008; Justesen et al., 2001). Fewer osteoblasts results in a reduction in bone formation, which fails to compensate for the bone lost during resorption. Although the number and activity of osteoclasts is aug- mented by estrogen deprivation during menopause, there is evi- dence that bone turnover declines in elderly men and women (Khosla and Riggs, 2005; Seeman, 2002). From a structural per- spective, these changes result in decreased trabecular bone, signif- icant cortical thinning and expansion of the marrow cavity, which is progressively infiltrated by fat (Duque and Troen, 2008; Seeman, 2002). At the molecular level, these changes are the consequence of complex interactions between growth factors, hormones, matrix molecules and the commitment of common precursor cells to one lineage or another (Chan and Duque, 2002). Research into the etiology and pathogenesis of osteoporosis has been advanced by the use of animal models to mimic these interactions (Priemel et al., 2002; Watanabe, 2008). Although osteopenia is a common feature in these models, the pathophysiology of their bone loss cor- relates poorly with that of age-related bone loss (Priemel et al., 2002). In fact, in an attempt to avoid the systemic changes to many organ systems that occur with aging, few studies have used purely aged animals (Priemel et al., 2002; Watanabe and Hishiya, 2005). The ovariectomized rodents are the most commonly used ani- mal model of osteopenia and osteoporosis (Watanabe and Hishiya, 2005). Their bone phenotype is characterized by low bone mass resulting from increased bone turnover associated with estrogen deficiency and elevated osteoclastic activity (Iwaniec et al., 2006). However, there is limited evidence that estrogen depriva- tion is actually a model of senile osteoporosis since, in contrast of what happens in the ovariectomized models, the ageing human skeleton is characterized by low bone mass, enhanced bone fragil- ity and increased fracture risk arising from a reduction in bone for- mation, uncompensated bone resorption, and an increase in bone marrow adipogenesis (Chan and Duque, 2002; Duque, 2008; Juste- sen et al., 2001; Seeman, 2002). In order to better understand the cellular and molecular mechanisms of senile osteoporosis, charac- terization of additional animal models are of great interest. 0531-5565/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2008.10.004 * Corresponding author. Address: Aging Bone Research Program, Nepean Clinical School, University of Sydney, Level 5, South Block, Nepean Hospital, Penrith, NSW 2750, Australia. Tel.: +61 2 4734 4279; fax: +61 2 4734 1817. E-mail address: gduque@med.usyd.edu.au (G. Duque). Experimental Gerontology 44 (2009) 183–189 Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero