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Sclerostin antibody augments the anabolic bone formation response in a mouse model of mechanical tibial loading

Morse, Morse Alyson and Schindeler, Aaron and McDonald, Michelle M and Kneissel, Michaela and Kramer, Ina and Little, David G (2017) Sclerostin antibody augments the anabolic bone formation response in a mouse model of mechanical tibial loading. Journal of bone and mineral research.. ISSN 1523-4681; 0884-0431

Abstract

Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β-catenin signaling,
results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl-
Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important
in modulating the response of bone to changes in its biomechanical environment. However, the
effects of Scl-Ab on mechanotransduction are unclear, and it was speculated that the loading
response may be altered for individuals receiving Scl-Ab therapy.
To address this, we carried out a 2 week study of tibial cyclic compressive loading on C57Bl/6
mice treated with vehicle or 100mg/kg/week Scl-Ab. Increases in bone volume, density, and
dynamic bone formation were seen with loading, and the anabolic response was further increased
by the combination of load and Scl-Ab. To investigate the underlying mechanism, gene profiling
by RNA sequencing (RNAseq) was performed on tibiae isolated from mice from all four
experimental groups. Major alterations in Wnt/β-catenin gene expression were seen with tibial
loading, however not with Scl-Ab treatment alone. Notably, the combination of load and Scl-Ab
elicited a synergistic response from a number of specific Wnt-related and mechanotransduction
factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling
pathway with combination treatment.
In summary, combination therapy had a more profound anabolic response than either Scl-Ab or
loading treatment alone. The Wnt/β-catenin and Rho GTPase pathways were implicated within
bone mechanotransduction, and support the concept that bone mechanotransduction is likely to
encompass a number of interconnected signaling pathways.

Item Type: Article
Keywords: Wnt/β-catenin/LRPs, Therapeutics, Anabolics, Bone QCT/μCT, Preclinical Studies
Date Deposited: 18 Nov 2017 00:45
Last Modified: 18 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/33383

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