Abstract
Summary
To investigate the role of Sirtuin1 in osteoporosis, Sirtuin1 was determined at the femoral neck in female patients undergoing hip operation for fractured hip or osteoarthritis. Reduced Sirtuin1 was found in osteoporotic patients. Pharmacologic activation of Sirtuin1 reduced sclerostin, an inhibitor of bone formation. Activation of Sirtuin1 may be a new direction to generate therapies for osteoporosis.
Introduction
The aim of the study are to investigate the role of Sirtuin1 (Sirt1), an anti-aging factor and a player in age-associated diseases, in osteoporotic hip fractures, and test the hypothesis that Sirt1 is a negative regulator of sclerostin, a bone formation inhibitor, in human femoral bone marrow mesenchymal cells (BM-MSCs).
Methods
Sirt1 and sclerostin were determined by western blot in bone samples obtained intra-operatively from the inferior medial cortex of the femoral neck (calcar region) in female patients undergoing partial hip replacement for fractured neck of femur (N = 10) or hip replacement for osteoarthritis (N = 8) (mean ± SD age 81 ± 8.1 vs. 68 ± 9.3 years; BMI 26.2 ± 3.6 vs. 25.9 ± 7.1 kg/m2 in osteoporotic and osteoarthritis patients). Calcar thickness and femoral bone mineral density (BMD) were determined preoperatively by X-ray using a digital TraumaCad™ software and DEXA. Femoral BM-MSCs were collected intra-operatively and treated with SRT3025, a Sirt1 activator. Sclerostin and dentin matrix acidic phosphoprotein (DMP1) were determined by western blot and messenger RNA (mRNA) expression of Lef1 and DMP1 was evaluated by quantitative real-time PCR.
Results
Osteoporotic (OP) patients had reduced cortical thickness, femoral neck, and total hip BMD compared to osteoarthritis (OA) patients. Calcar Sirt1 expression was significantly reduced, while sclerostin was markedly increased in OP compared to OA patients. Sirt1 and sclersotin expressions were inversely correlated (r = −0.49, P = 0.047). SRT3025 administration down-regulated sclerostin and up-regulated DMP1 protein level and increased LEF1 and DMP1 mRNA expressions in OP patient-derived BM-MSCs.
Conclusions
Reduced femoral neck Sirt1 may play a role in osteoporotic hip fractures in part via influencing local sclerostin expression. The therapeutic potential of Sirt1 activation in osteoporosis warrants further investigation.
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Acknowledgments
This work was supported by Israel Science Foundation Grant 842/10 to RDP and the Joint Research Fund of the Hebrew University to MEH. We thank the late Raymond Kaplan and the Bnai Brith Leo Baeck London Lodge for their support of osteoporosis research. We thank Sirtris/GSK for SRT3025. Authors’ roles: study design MEH, OS, ECK, and RDP; study conduct MEH, IG, HA, ECK, AK, VD, and OY; data interpretation MEH, IG, ECK, HA, OS, and RDP; and drafting manuscript MEH, OS, IG, and RDP. OS and RDP contributed equally to the development of hypotheses, the analyses, and interpretation of the results and are responsible for the integrity of the data analysis.
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The study HMO-361-06 was approved by the institutional ethical committee, and all participants signed informed consent.
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Madi El-Haj, Irina Gurt, Einav Cohen-Kfir, Vivek Dixit, Hanna Artsi, Leonid Kandel, Oran Yakubovsky, Ori Safran, and Rivka Dresner-Pollak declare that they have no conflict of interest.
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M. El-Haj, I. Gurt, O. Safran and R. Dresner-Pollak contributed equally to this work.
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El-Haj, M., Gurt, I., Cohen-Kfir, E. et al. Reduced Sirtuin1 expression at the femoral neck in women who sustained an osteoporotic hip fracture. Osteoporos Int 27, 2373–2378 (2016). https://doi.org/10.1007/s00198-016-3536-4
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DOI: https://doi.org/10.1007/s00198-016-3536-4