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Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

Ryser MD, Qu Y, Komarova SV - PLoS Comput. Biol. (2012)

Bottom Line: Consistently, systemic application of OPG decreases metastatic tumor burden in bone.However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth.The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.

ABSTRACT
Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

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Interactions taken into account in the study.Two cell types are considered: cancer cells and osteoclasts. Osteoclasts positively affect cancer cells by providing space for tumor growth. Parathyroid hormone-related protein (PTHrP) produced by metastasizing cancer cells induces the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in bone tissue. RANKL in turn is a potent stimulator of osteoclasts and bone resorption. Osteoprotegerin (OPG) is a decoy receptor of RANKL which binds and eliminates RANKL.
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pcbi-1002703-g001: Interactions taken into account in the study.Two cell types are considered: cancer cells and osteoclasts. Osteoclasts positively affect cancer cells by providing space for tumor growth. Parathyroid hormone-related protein (PTHrP) produced by metastasizing cancer cells induces the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in bone tissue. RANKL in turn is a potent stimulator of osteoclasts and bone resorption. Osteoprotegerin (OPG) is a decoy receptor of RANKL which binds and eliminates RANKL.

Mentions: Once a secondary tumor starts growing in the bone environment, its expansion is geometrically constrained by the presence of inelastic bone tissue. Physiologically, bone is remodeled through the process where old or damaged tissue is resorbed by cells specialized in bone destruction, osteoclasts, and new bone is produced by specialized bone-forming osteoblasts [3]–[5]. The RANK/RANKL/OPG pathway plays a crucial role in physiological bone remodeling. Receptor activator of nuclear factor kappa-B (RANK) is expressed by osteoclast precursors and mature osteoclasts. During remodeling, RANK ligand (RANKL) expressed by cells of the osteoblasic lineage stimulates osteoclast formation and directs osteoclasts towards sites of microdamage. Once osteoclasts have removed the old tissue, they move forward and recruit osteblasts, which in turn fill the previously resorbed trench with osteoid. The latter eventually mineralizes, and the process of mass-neutral bone renewal is complete. Mature osteoblasts also produce the soluble decoy receptor osteoprotegerin (OPG), which binds to RANKL and hence prevents it from interaction with RANK [3]. By producing OPG, osteoblasts have the ability to manipulate the RANKL concentration and gradient which control osteoclast allocation and steering [6]. Since cancer cells are unable to resorb bone, the only way for the tumor to expand is to trigger osteoclasts [7]. Cancer cells produce factors such as the parathyroid hormone-related protein (PTHrP), which induce the production of osteoclast-stimulating RANKL by osteoblasts, osteocytes and stromal cells [1]. The mostly membrane-bound RANKL binds to its receptor RANK, expressed on osteoclasts and their precursors, thus inducing osteoclast differentiation and stimulating resorptive activity. The resulting osteolysis provides in turn more space for the growing tumor – thereby closing the so-called ‘vicious cycle’ of bone resorption and tumor growth (Figure 1).


Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

Ryser MD, Qu Y, Komarova SV - PLoS Comput. Biol. (2012)

Interactions taken into account in the study.Two cell types are considered: cancer cells and osteoclasts. Osteoclasts positively affect cancer cells by providing space for tumor growth. Parathyroid hormone-related protein (PTHrP) produced by metastasizing cancer cells induces the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in bone tissue. RANKL in turn is a potent stimulator of osteoclasts and bone resorption. Osteoprotegerin (OPG) is a decoy receptor of RANKL which binds and eliminates RANKL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475686&req=5

pcbi-1002703-g001: Interactions taken into account in the study.Two cell types are considered: cancer cells and osteoclasts. Osteoclasts positively affect cancer cells by providing space for tumor growth. Parathyroid hormone-related protein (PTHrP) produced by metastasizing cancer cells induces the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in bone tissue. RANKL in turn is a potent stimulator of osteoclasts and bone resorption. Osteoprotegerin (OPG) is a decoy receptor of RANKL which binds and eliminates RANKL.
Mentions: Once a secondary tumor starts growing in the bone environment, its expansion is geometrically constrained by the presence of inelastic bone tissue. Physiologically, bone is remodeled through the process where old or damaged tissue is resorbed by cells specialized in bone destruction, osteoclasts, and new bone is produced by specialized bone-forming osteoblasts [3]–[5]. The RANK/RANKL/OPG pathway plays a crucial role in physiological bone remodeling. Receptor activator of nuclear factor kappa-B (RANK) is expressed by osteoclast precursors and mature osteoclasts. During remodeling, RANK ligand (RANKL) expressed by cells of the osteoblasic lineage stimulates osteoclast formation and directs osteoclasts towards sites of microdamage. Once osteoclasts have removed the old tissue, they move forward and recruit osteblasts, which in turn fill the previously resorbed trench with osteoid. The latter eventually mineralizes, and the process of mass-neutral bone renewal is complete. Mature osteoblasts also produce the soluble decoy receptor osteoprotegerin (OPG), which binds to RANKL and hence prevents it from interaction with RANK [3]. By producing OPG, osteoblasts have the ability to manipulate the RANKL concentration and gradient which control osteoclast allocation and steering [6]. Since cancer cells are unable to resorb bone, the only way for the tumor to expand is to trigger osteoclasts [7]. Cancer cells produce factors such as the parathyroid hormone-related protein (PTHrP), which induce the production of osteoclast-stimulating RANKL by osteoblasts, osteocytes and stromal cells [1]. The mostly membrane-bound RANKL binds to its receptor RANK, expressed on osteoclasts and their precursors, thus inducing osteoclast differentiation and stimulating resorptive activity. The resulting osteolysis provides in turn more space for the growing tumor – thereby closing the so-called ‘vicious cycle’ of bone resorption and tumor growth (Figure 1).

Bottom Line: Consistently, systemic application of OPG decreases metastatic tumor burden in bone.However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth.The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.

ABSTRACT
Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

Show MeSH
Related in: MedlinePlus