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Effect of Sclerostin Antibody Treatment in a Mouse Model of Severe Osteogenesis Imperfecta

Roschger, Andreas and Roschger, Paul and Keplinger, Petra and Klaushofer, Klaus and Abdullah, Sami and Kneissel, Michaela and Rauch, Frank (2014) Effect of Sclerostin Antibody Treatment in a Mouse Model of Severe Osteogenesis Imperfecta. Bone.

Abstract

Children with Osteogenesis imperfecta (OI) still suffer from frequent fractures, despite bisphosphonate treatment. Thus new therapeutic approaches are needed. Sclerostin is a protein that is thought to inhibit bone formation. Treatment with sclerostin antibodies (SclAB) increases bone mass in animal models and in clinical trials and may be a rational therapy for OI as well.

Transgenic (TgOI) Col1a1Jrt/+ mice were generated being a model of OI type IV. 8 weeks old TgOI (n=8) and wild type (Wt) (n=8) were analyzed after 4 weeks of SclAB treatment and compared to untreated animals (n=7, n=8). The bone mineralization density distribution (BMDD) of the cortical (Ct), metaphyseal spongiosa (MS) and epiphyseal spongiosa (ES) in the distal femur was measured by quantitative backscattered electron imaging. Additionally microCT parameters of the femurs were obtained.

TgOI mice exhibit increased bone matrix mineralization compared to Wt (most frequently occurring Ca concentration: Ct:+6.8% MS:+5.2% ES:+8.2%, p<0.001). The mineralization was also more homogenous in Ct. This fits previous findings in OI models. The percentage of lowly mineralized areas was increased in MS and ES most likely due to the decrease of bone volume (-86.3%, p<0.001).

Treatment with SclAB of Wt and TgOI mice overall led to shifts in the BMDD of the spongiosa towards higher and more homogenously mineralized bone. This is consistent with the observed decrease in percentage of lowly mineralized regions reflecting the increase in bone volume due to SclAB treatment. 2-Way ANOVA tests revealed no interaction between genotype and treatment. After treatment, BV/TV of the Wt (+77.7%, p<0.001) and the TgOI (+65.9%, p=0.02) animals were elevated. Wt/SclAB and the TgOI/SclAB mice exhibit more bone volume and a similar increase in matrix mineralization compared to the corresponding untreated animals.

Therefore we conclude, that SclAB treatment has the similar effect on mineralization in TgOI and Wt mice.

Item Type: Article
Keywords: bone formation; osteogenesis imperfecta; quantitative backscattered electron imaging; sclerostin
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/20957

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