title: Reduced Sirtuin1 expression at the femoral neck in women who sustained an osteoporotic hip fracture.
abstract: 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.
  
  
  
  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).
  
  
  
  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/m(2) 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: El-Haj
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Gurt
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Cohen-Kfir
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Dixit
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel.|Hadassah-Hebrew University Medical School, Jerusalem, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Artsi
authors.affiliation: Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Kandel
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel.|Hadassah-Hebrew University Medical School, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Yakubovsky
authors.affiliation: Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Safran
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem, 91120, Israel. rivkap@hadassah.org.il.
authors.forename: R
authors.initials: R
authors.lastname: Dresner-Pollak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D015519:Bone Density; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005272:Femur Neck / Q000378:metabolism*; D005819:Genetic Markers; D006620:Hip Fractures / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D010003:Osteoarthritis / Q000601:surgery; D010024:Osteoporosis / Q000601:surgery; D058866:Osteoporotic Fractures / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D010750:Phosphoproteins; C422903:SOST protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Femoral neck; Osteoarthritis; Osteoporotic hip fracture; Sclerostin; Sirtuin1