Age-related bone loss in the LOU/c rat model of healthy ageing

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 quantitative 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 undecalcified 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.

[1]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  L. Raisz Pathogenesis of osteoporosis: concepts, conflicts, and prospects. , 2005, The Journal of clinical investigation.

[3]  Dominique Meynial-Denis,et al.  The LOU/c/jall rat as an animal model of healthy aging? , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  H. Chen,et al.  Ultrastructural changes in bones of the senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. , 2004, Histology and histopathology.

[5]  M. Kuro-o,et al.  Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. , 1999, The Journal of clinical investigation.

[6]  A. Hishiya,et al.  Progeroid syndrome as a model for impaired bone formation in senile osteoporosis , 2004, Journal of Bone and Mineral Metabolism.

[7]  E. Quenneville,et al.  Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. , 2006, Human molecular genetics.

[8]  B. Riggs,et al.  Pathophysiology of age-related bone loss and osteoporosis. , 2005, Endocrinology and metabolism clinics of North America.

[9]  L. Mosekilde,et al.  Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis , 2004, Biogerontology.

[10]  D. Kalu,et al.  Age-related changes in bone mineral content and density in intact male F344 rats. , 2002, Bone.

[11]  J. Bariéty,et al.  Longitudinal study of solute excretion and glomerular ultrastructure in an experimental model of aging rats free of kidney disease. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[12]  K. Kovacs,et al.  Pituitary adenomas in old Sprague-Dawley rats: a histologic, ultrastructural, and immunocytochemical study. , 1984, Journal of the National Cancer Institute.

[13]  S. Fukuda,et al.  Age-related changes in bone mineral density, cross-sectional area and the strength of long bones in the hind limbs and first lumbar vertebra in female Wistar rats. , 2004, The Journal of veterinary medical science.

[14]  Sharmila Majumdar,et al.  Changes in Bone Structure and Mass With Advancing Age in the Male C57BL/6J Mouse , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  J. Epelbaum,et al.  Preserved memory capacities in aged Lou/C/Jall rats , 2010, Neurobiology of Aging.

[16]  B. Troen,et al.  Understanding the Mechanisms of Senile Osteoporosis: New Facts for a Major Geriatric Syndrome , 2008, Journal of the American Geriatrics Society.

[17]  J. Epelbaum,et al.  Delayed Age-Associated Decrease in Growth Hormone Pulsatile Secretion and Increased Orexigenic Peptide Expression in the Lou C/Jall Rat , 2005, Neuroendocrinology.

[18]  Andrei L. Turinsky,et al.  Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft. , 2007, Bone.

[19]  A. Schilling,et al.  Osteopenic mice: animal models of the aging skeleton. , 2002, Journal of musculoskeletal & neuronal interactions.

[20]  D. Kalu,et al.  Male rodent model of age-related bone loss in men. , 2001, Bone.

[21]  G. Duque,et al.  Age-Related Bone Loss: Old Bone, New Facts , 2002, Gerontology.

[22]  E Panagiotopoulos,et al.  Evaluation of modal damping factor as a diagnostic tool for osteoporosis and its relation with serum osteocalcin and collagen I N-telopeptide for monitoring the efficacy of alendronate in ovariectomized rats. , 2006, Journal of pharmaceutical and biomedical analysis.

[23]  M. Macoritto,et al.  1,25(OH)2D3 inhibits bone marrow adipogenesis in senescence accelerated mice (SAM-P/6) by decreasing the expression of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) , 2004, Experimental Gerontology.

[24]  S. Fukuda,et al.  Age-related changes in bone mineral density, cross-sectional area and strength at different skeletal sites in male rats. , 2002, The Journal of veterinary medical science.

[25]  K. Seuwen,et al.  Enhanced Marrow Adipogenesis and Bone Resorption in Estrogen-Deprived Rats Treated with the PPARgamma Agonist BRL49653 (Rosiglitazone) , 2004, Calcified Tissue International.

[26]  M. Skalicky,et al.  Bone structure and metabolism in a rodent model of male senile osteoporosis , 2007, Experimental Gerontology.

[27]  S. Richard,et al.  Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss , 2005, PLoS genetics.

[28]  U. Iwaniec,et al.  Strain‐Dependent Variations in the Response of Cancellous Bone to Ovariectomy in Mice , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  P Gaudreau,et al.  Regulation of the Pituitary Growth Hormone‐Releasing Hormone Receptor in Ageing Male and Female LOU Rats: New Insights into Healthy Ageing , 2005, Journal of neuroendocrinology.

[30]  G. Duque Bone and fat connection in aging bone , 2008, Current opinion in rheumatology.

[31]  Ego Seeman,et al.  Pathogenesis of bone fragility in women and men , 2002, The Lancet.

[32]  A. Hishiya,et al.  Mouse models of senile osteoporosis. , 2005, Molecular aspects of medicine.