Adaptive response of bone to mechanical strain in a mouse model of myeloma bone disease

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Bones adapt to changing loads (so-called modeling) and have the capacity for self-repair and renewal (remodeling). These anabolic processes allow bones to perform their mechanical functions successfully over long periods of time. Local adaptive responses of bones to mechanical loading have been demonstrated most dramatically in athletes under training. Mechanical loading in form of exercise has further shown promising results in cancer patients to maintain bone structural strength and to prevent bone loss. We have preliminary data in our MOPC315.BM mouse model for multiple myeloma (MM) bone disease which demonstrate that already established osteolytic lesions decrease under conditions of mechanical loading. MM is the second most common hematological neoplasia in the USA and Europe with characteristic osteolytic bone structure changes. The goal of this project is a mechano-biological understanding of how mechanical stimulation influences (re)modeling processes in the bone tumor microenvironment of established MM and during onset of MM bone disease. Our results will help us to determine the efficacy of mechanical stimulation as an anabolic therapy to treat MM bone disease. We hypothesize that mechanical stimulation will increase bone formation and decrease bone resorption by activating known bone (re)modeling pathways (such as RANK/RANKL and Wnt), which are deleteriously altered by MM cells in bone. We study whether the osteoresorptive pathway Notch is involved in mechanotransduction after mechanical stimulation. We will specifically investigate how mechanical loading alone and in combination with inhibition of Notch controls MM bone (re)modeling processes. For analysis of mechanotransduction in vitro we use a small scale bioreactor system and co-cultivate human mesenchymal stem cells and MM cells under conditions of mechanical strain. Noninvasive in-vivo controlled mechanical loading will be administered to MOPC315.BM mice tibiae after already established osteolytic MM bone disease and simultaneously while MM tumor engraftment and bone disease are occurring. The bone (re)modelling response to mechanical loading during MM will be investigated by longitudinal in vivo microCT imaging as well as conventional histomorphometric analysis. The molecular mechanisms of the bone (re)modelling processes will be analyzed using a combination of histological, biochemical and molecular genetic methods. This study will contribute to a fundamental understanding of the mechano-biological and molecular mechanisms of anabolic bone adaptation during MM bone disease in response to mechanical stimuli. The knowledge gained from these experiments will aid in the development of novel anabolic strategies for treating and preventing MM bone disease.