Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta

被引:81
作者
Roschger, Andreas [1 ]
Roschger, Paul [1 ]
Keplingter, Petra [1 ]
Klaushofer, Klaus [1 ]
Abdullah, Sami [2 ,3 ]
Kneissel, Michaela [4 ]
Rauch, Frank [2 ,3 ]
机构
[1] Hanusch Hosp, Ludwig Boltzmann Inst Osteol, WGKK & AUVA Trauma Ctr Meidling, Vienna, Austria
[2] Shriners Hosp Children, Montreal, PQ H3G 1A6, Canada
[3] McGill Univ, Montreal, PQ, Canada
[4] Novartis Inst Biomed Res, Musculoskeletal Dis Area, Basel, Switzerland
关键词
Bone formation; Osteogenesis imperfecta; Quantitative backscattered electron imaging; Sclerostin; BONE HISTOMORPHOMETRY; ALENDRONATE TREATMENT; MINERAL DENSITY; HIGH-AFFINITY; CHILDREN; VALIDATION; ADULTS; SIZE;
D O I
10.1016/j.bone.2014.06.015
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Osteogenesis imperfecta (OD is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4 weeks in male Col1a1(Jrt)/+ mice, a model of severe dominant OI, starting either at 4 weeks (growing mice) or at 20 weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type 1) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+ mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:182 / 188
页数:7
相关论文
共 28 条
[1]   WNT signaling in bone homeostasis and disease: from human mutations to treatments [J].
Baron, Roland ;
Kneissel, Michaela .
NATURE MEDICINE, 2013, 19 (02) :179-192
[2]   First Mouse Model for Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome [J].
Chen, Frieda ;
Guo, Ruolin ;
Itoh, Shousaku ;
Moreno, Luisa ;
Rosenthal, Esther ;
Zappitelli, Tanya ;
Zirngibl, Ralph A. ;
Flenniken, Ann ;
Cole, William ;
Grynpas, Marc ;
Osborne, Lucy R. ;
Vogel, Wolfgang ;
Adamson, Lee ;
Rossant, Janet ;
Aubin, Jane E. .
JOURNAL OF BONE AND MINERAL RESEARCH, 2014, 29 (06) :1412-1423
[3]   Measurement of C-terminal telopeptide of type I collagen (CTX) in serum [J].
Chubb, S. A. Paul .
CLINICAL BIOCHEMISTRY, 2012, 45 (12) :928-935
[4]   Lrp5 functions in bone to regulate bone mass [J].
Cui, Yajun ;
Niziolek, Paul J. ;
MacDonald, Bryan T. ;
Zylstra, Cassandra R. ;
Alenina, Natalia ;
Robinson, Daniel R. ;
Zhong, Zhendong ;
Matthes, Susann ;
Jacobsen, Christina M. ;
Conlon, Ronald A. ;
Brommage, Robert ;
Liu, Qingyun ;
Mseeh, Faika ;
Powell, David R. ;
Yang, Qi M. ;
Zambrowicz, Brian ;
Gerrits, Han ;
Gossen, Jan A. ;
He, Xi ;
Bader, Michael ;
Williams, Bart O. ;
Warman, Matthew L. ;
Robling, Alexander G. .
NATURE MEDICINE, 2011, 17 (06) :684-U73
[5]   Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee [J].
Dempster, David W. ;
Compston, Juliet E. ;
Drezner, Marc K. ;
Glorieux, Francis H. ;
Kanis, John A. ;
Malluche, Hartmut ;
Meunier, Pierre J. ;
Ott, Susan M. ;
Recker, Robert R. ;
Parfitt, A. Michael .
JOURNAL OF BONE AND MINERAL RESEARCH, 2013, 28 (01) :1-16
[6]   New perspectives on osteogenesis imperfecta [J].
Forlino, Antonella ;
Cabral, Wayne A. ;
Barnes, Aileen M. ;
Marini, Joan C. .
NATURE REVIEWS ENDOCRINOLOGY, 2011, 7 (09) :540-557
[7]   CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII [J].
Fratzl-Zelman, N. ;
Morello, R. ;
Lee, B. ;
Rauch, F. ;
Glorieux, F. H. ;
Misof, B. M. ;
Klaushofer, K. ;
Roschger, P. .
BONE, 2010, 46 (03) :820-826
[8]   Mineral particle size in children with osteogenesis imperfecta type I is not increased independently of specific collagen mutations [J].
Fratzl-Zelman, Nadja ;
Schmidt, Ingo ;
Roschger, Paul ;
Glorieux, Francis H. ;
Klaushofer, Klaus ;
Fratzl, Peter ;
Rauch, Frank ;
Wagermaier, Wolfgang .
BONE, 2014, 60 :122-128
[9]   Age- and genotype-dependence of bone material properties in the osteogenesis imperfecta murine model (oim) [J].
Grabner, B ;
Landis, WJ ;
Roschger, P ;
Rinnerthaler, S ;
Peterlik, H ;
Klaushofer, K ;
Fratzl, P .
BONE, 2001, 29 (05) :453-457
[10]  
Jacobsen CM., 2014, J Bone Miner Res