A novel humanized RANKL transgenic mouse model of osteoporosis

May 31, 2017 | Autor: Vagelis Rinotas | Categoria: Engineering, Biological Sciences, Bone, Transgenic Mouse Technology
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Abstracts / Bone 44 (2009) S339–S450

(L1–L4) and right femoral neck (FN) were measured with dual energy X-ray absorptiometry. Data were expressed as mean (±SD). Statistical analyses were done with SPSS for windows version 12.0. Results: Probands with DS had significantly lower height and weight than healthy controls, but did not differ in BMI. FN-BMD (p < 0.001) and L1–L4-BMD (p < 0.001) as well as FN Z-score (p < 0.001) and L1–L4 Z-score (p < 0.001) of DS group were significantly lower than in control group. All measured biochemical parameters and PTH were in normal range in both groups. Patients with DS had significantly higher ALP (p < 0.001), OC (p < 0.001), CTx (p < 0.001), OPG (p < 0.01) and CatK (p < 0.001). Bivariate analysis demonstrated significant inverse correlations between FN-BMD and OC (r = − 0.252, p < 0.03), CTx (r = − 0.433, p < 0.001), ALP (r = −0.245, p < 0.03) and CatK (r = −0.213, p < 0.05) and between L1– L4-BMD and OC (r = −0,219, p < 0.05), CTx (r = −0.438, p < 0.001), ALP (r = −0.238, p < 0.03), CatK (r = −0.224, p < 0.04) and OPG (r = −0.269, p < 0.02). Conclusions: On the basis of our results we can suggest that individuals with DS are at high risk for low BMD in femoral neck and lumbar spine. Our study also provides the evidence that bone markers and cytokines are closely related to bone turnover process in Down syndrome. This work was supported by Ministry of Health of Slovakia No.2005/39-SZU-17. Conflict of interest: None declared. doi:10.1016/j.bone.2009.03.357

P446 Effects of treadmill running and swimming exercise on bone microstructure in rats with ovariectomy A. Minematsua,*, Y. Nakamorib, K. Hayakawac, Y. Nishiia a Health Science, Kio University, Kitakatsuragi-gun, Japan b Rehabilitation, Ozawa Hospital, Kyoto, Japan c Rehabilitation, Haruki Hospital, Kishiwada, Japan Background: Physical activity is effective on prevention from bone loss. But the effects differ by the activity conditions, in particular running and swimming. This study investigated the effects of treadmill running and swimming exercise on bone microstructure in ovariectomized rats. Materials and methods: Twenty-four female rats aged 10 weekold were divided into 4 groups randomly, and they were either shamoperated (SHAM) or ovariectomized (OVX). Two of OVX group started to run on the treadmill (TR) or swim in the pool (SE) at a week after the operation. Running condition was at 18 m/min, for 20 min, on 5 days/week for 12 weeks, and swimming condition was at 18 m/min (a current), for 20 min, on 5 days/week, at 30 °C, for 12 weeks. After the experiment, tibias of all rats were dissected out. Micro CT scanning was used to determine morphological indices of bone volume and architecture in the metaphysical region of the proximal tibia. This region spanned 2 mm, with the first slice starting 0.5 mm proximal from growth plate. Bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), trabecular space (Tb.Spac), connectivity density (Conn.D), the structural model index (SMI), and trabecular bone pattern factor (TBPf) of trabecular bones were measured with bone analysis soft, TRI BON 3D. In statistical analysis, one-way ANOVAs followed by Tukey–Kramer tests evaluated differences in bone quantity and micro architecture of SHAM, OVX, TR and SE groups. A significance level of p = 0.05 was set. This study was carried out in accordance with the Guide for Animal Experimentation, Kio University and the Committee of Research Facilities of Laboratory Animal Science, Kio University.

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Results: BV/TV, Tb.Th, Th.N, and Conn.D in TR rats were significantly higher than those in OVX rats. Tb.N and Conn.D in SE rats were significantly higher than those in OVX rats. Tb.Spac in TR and SE groups was significantly lower than that in OVX group. BV/TV, Th.N, Conn.D and TBPf were low, and Tb.Sp, Tb.Spac and SMI were high significantly in TR and SE groups, compared with SHAM group. Conclusions: TR and SE could prevent from bone loss, and TR was more effective than SE. Especially, Tb.Th was kept in TR rats. It was suggested that bone loss was inhibited by exercise and this differs by the loading situation. Conflict of interest: None declared. doi:10.1016/j.bone.2009.03.358

P447 A novel humanized RANKL transgenic mouse model of osteoporosis A. Niti*, V. Rinotas, E. Douni Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece Therapeutic targeting of RANKL/RANK/OPG interactions and signaling holds great promise for the treatment of bone diseases such as osteoporosis, rheumatoid arthritis, and bone metastasis. However, a mouse model overexpressing human RANKL is currently missing. Our goal is to model human RANKL-mediated pathologies in transgenic mice in order a) to study the pathogenic mechanisms and b) to evaluate novel inhibitors of human RANKL at preclinical level. Therefore, we have recently generated five independent humanized RANKL transgenic lines carrying the human RANKL genomic region. A striking skeletal phenotype characterized by severe kyphosis and impaired locomotion activity was observed in the highest copy number human RANKL transgenic founder. At necropsy, we observed multiple bone fractures and haematomas at long bones whereas histological examination confirmed fractures and revealed numerous osteoclasts with extended destruction of the growth plate, the trabecular and the cortical bones. We are currently characterizing the expression profile of human RANKL in the different transgenic mouse lines and investigating whether the levels of RANKL expression are correlated with disease severity. Apart from the skeletal system, we also examine if RANKL overexpressing mice develop other pathologies such as arterial calcification or immunological diseases. The broad clinical trial experience so far indicates that inhibition of RANKL effectively decreases bone resorption with minimal side effects in human patients. Therefore, these novel humanized RANKL transgenic mice represent a unique tool for understanding the pathogenic mechanisms that cause bone resorption and for the evaluation of novel therapeutic approaches targeting RANKL-mediated pathologies such as osteoporosis. Conflict of interest: None declared. doi:10.1016/j.bone.2009.03.359

P448 Renal safety and impact on the metabolism of bone after infusion of aclasta A. Reda*, M.G. Bartoletti, G. Davola U O Rehabilitation, A S P Cosenza, Rogliano, Italy Introduction: Zoledronic acid at 5 mg, once-yearly infusion, is the most recent drug approved for treatment of PMO. This observational

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