Computational Modeling of Interactions between Multiple Myeloma and the Bone Microenvironment

Yan Wang,Pascal R Buenzli,Colin R Dunstan,David W Smith,Peter Pivonka,Ying Xu

doi:10.1371/journal.pone.0027494

Yan Wang, Pascal R Buenzli + Show 4 more

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https://doi.org/10.1371/journal.pone.0027494

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Abstract

Multiple Myeloma (MM) is a B-cell malignancy that is characterized by osteolytic bone lesions. It has been postulated that positive feedback loops in the interactions between MM cells and the bone microenvironment form reinforcing ‘vicious cycles’, resulting in more bone resorption and MM cell population growth in the bone microenvironment. Despite many identified MM-bone interactions, the combined effect of these interactions and their relative importance are unknown. In this paper, we develop a computational model of MM-bone interactions and clarify whether the intercellular signaling mechanisms implemented in this model appropriately drive MM disease progression. This new computational model is based on the previous bone remodeling model of Pivonka et al. [1], and explicitly considers IL-6 and MM-BMSC (bone marrow stromal cell) adhesion related pathways, leading to formation of two positive feedback cycles in this model. The progression of MM disease is simulated numerically, from normal bone physiology to a well established MM disease state. Our simulations are consistent with known behaviors and data reported for both normal bone physiology and for MM disease. The model results suggest that the two positive feedback cycles identified for this model are sufficient to jointly drive the MM disease progression. Furthermore, quantitative analysis performed on the two positive feedback cycles clarifies the relative importance of the two positive feedback cycles, and identifies the dominant processes that govern the behavior of the two positive feedback cycles. Using our proposed quantitative criteria, we identify which of the positive feedback cycles in this model may be considered to be ‘vicious cycles’. Finally, key points at which to block the positive feedback cycles in MM-bone interactions are identified, suggesting potential drug targets.

Highlights

Multiple Myeloma (MM) is a B-cell malignancy associated with high morbidity and short survival duration post-diagnosis. 60– 70% of MM patients have bone involvement at the time of diagnosis (60% of them with bone pain and 25% of them with bone fracture), and 90% of MM patients will develop bone lesions during the course of the disease [2,3,4,5]
One important difference is that while it is assumed that OPG is secreted from osteoblast precursors and RANKL is expressed on active osteoblasts in Lemaire et al [19], in Pivonka et al [1] these assumptions are reversed (i.e., RANKL is expressed on osteoblast precursors and OPG is secreted by active osteoblasts)
To include the interactions between MM cells and bone cells adequately, this bone remodeling model needs to be extended to incorporate the mechanisms of transforming growth factor b (TGF-b)-stimulated IL-6 production by Bone marrow stromal cells (BMSC) and IL-6-stimulated RANKL expression on the surface of osteoblast precursors

Summary

Introduction

Multiple Myeloma (MM) is a B-cell malignancy associated with high morbidity and short survival duration post-diagnosis. 60– 70% of MM patients have bone involvement at the time of diagnosis (60% of them with bone pain and 25% of them with bone fracture), and 90% of MM patients will develop bone lesions during the course of the disease [2,3,4,5]. Multiple Myeloma (MM) is a B-cell malignancy associated with high morbidity and short survival duration post-diagnosis. MM can be associated with a systematic thinning of bone or with the formation of focal osteolytic lesions [6]. The bone lesions result in osteopenia and pathologic fractures (i.e., compression fractures of the spine), which significantly impact on patient morbidity, performance status (including immobility, loss of independence and loss of dignity) and survival duration [3]. Coordinated coupling between osteoclast and osteoblast activity is necessary to maintain the balance between bone resorption and bone formation in adults [7,8]. Coordination between osteoclasts and osteoblasts is dysregulated in several disease, such as osteoporosis [9] and Paget’s disease [10], resulting in an imbalance between bone resorption and bone formation

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