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Myeloma bone disease.

Sanderson RD, Epstein J - J. Bone Miner. Res. (2009)

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sanderson@uab.edu

ABSTRACT

Bone disease is a characteristic feature of myeloma and causes devastating side effects that impact patient quality of life and survival. New findings over the last several years have led to a better understanding of the molecular mechanisms regulating bone disease including the understanding that myeloma bone disease results from hyperstimulation of osteoclastogenesis and inhibition of osteoblastogenesis. From these mechanistic findings, promising new therapies including bortezomib and denosumab have evolved and give hope for lessening the impact of osteolytic bone disease in myeloma. New therapies such as anti-DKK1 antibodies are on the horizon. Despite these advances, lingering questions remain that need to be addressed. Why in a small minority of patients do osteoblasts near tumor foci continue to survive and proliferate, whereas in most patients osteoblastogenesis is inhibited? Can combinations of bone preserving and bone forming therapies lead to repair of osteolytic lesions in myeloma? To what extent do myeloma tumor cells exhibit direct osteolytic effects separate from osteoclasts, and how can these effects be diminished? Tackling these and other remaining mechanistic questions will lead to even better therapeutic approaches to controlling myeloma bone disease.

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Mechanisms of myeloma-mediated bone destruction. The cartoon depicts a myeloma lesion and the events that occur, leading to formation of an osteolytic lesion. (1) Myeloma cells secrete DKK1 and FRP2 that inhibit Wnt pathway signaling, thus blocking osteoblastogenesis. (2) RANKL (blue triangles) expression on the surface of osteoblasts and bone marrow stromal cells is elevated, and expression of OPG (orange circles) is suppressed. In addition, OPG binds to syndecan-1 on the surface of myeloma cells and is internalized and degraded further shifting the balance toward osteoclastogenesis. (3) Myeloma cells express high levels of either cell surface or soluble RANKL. (4) The high levels of RANKL in the lesion lead to hyperstimulation of myeloid precursor differentiation into osteoclasts. Once mature, the osteoclasts degrade bone and release factors (green triangles) that stimulate myeloma growth. The net effect of these processes is extensive loss of bone at sites of myeloma foci leading to radiologically identifiable osteolytic lesions as shown in the X-ray on the right (arrow points to lesion).
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fig01: Mechanisms of myeloma-mediated bone destruction. The cartoon depicts a myeloma lesion and the events that occur, leading to formation of an osteolytic lesion. (1) Myeloma cells secrete DKK1 and FRP2 that inhibit Wnt pathway signaling, thus blocking osteoblastogenesis. (2) RANKL (blue triangles) expression on the surface of osteoblasts and bone marrow stromal cells is elevated, and expression of OPG (orange circles) is suppressed. In addition, OPG binds to syndecan-1 on the surface of myeloma cells and is internalized and degraded further shifting the balance toward osteoclastogenesis. (3) Myeloma cells express high levels of either cell surface or soluble RANKL. (4) The high levels of RANKL in the lesion lead to hyperstimulation of myeloid precursor differentiation into osteoclasts. Once mature, the osteoclasts degrade bone and release factors (green triangles) that stimulate myeloma growth. The net effect of these processes is extensive loss of bone at sites of myeloma foci leading to radiologically identifiable osteolytic lesions as shown in the X-ray on the right (arrow points to lesion).

Mentions: In myeloma, osteoclasts are hyperstimulated predominantly because of dysregulation of three TNF family members: RANK, its ligand (RANKL), and osteoprotegerin (OPG). The binding of RANKL to RANK that is present on the surface of myeloid precursors is needed for differentiation of the precursors into osteoclasts. The activation of RANK is antagonized when soluble OPG binds to RANKL, thereby preventing RANKL activation of RANK. This dampens the rate of osteoclastogenesis. In normal bone, the RANK/RANKL/OPG system works in concert to balance bone turnover and maintain normal homeostasis. In myeloma, both the tumor cells and the bone marrow stromal cells can produce osteoclast-activating factors, thereby shifting the balance toward enhanced osteoclastogenesis and bone destruction. This often occurs within the local tumor microenvironment where osteoclast numbers are seen to be elevated in areas adjacent to myeloma tumor cells. RANKL production is elevated in the bone marrow stroma in myeloma, and in addition, the tumor cells can also express RANKL(8–13) (Fig. 1). High expression levels of membrane-associated RANKL on myeloma cells has been correlated with the presence of multiple bone lesions in myeloma patients.(12,13) In addition, the membrane form of RANKL can be released by proteases. This released, soluble form of RANKL can diffuse away from the local tumor environment to promote widespread osteoclast activation, thereby contributing to systemic bone loss in myeloma.(14) Interestingly, although myeloma cells do not produce OPG, they can diminish the effect that OPG has on inhibiting osteoclastogenesis. This occurs when the heparan sulfate proteoglycan syndecan-1 on the surface of myeloma cells binds to OPG, leading to internalization and degradation of the OPG.(15) Because syndecan-1 is expressed at high levels on most myeloma tumor cells, the binding and degradation of OPG may be a substantial contributor to the bone-degrading phenotype of myeloma. Moreover, clipping of the heparan sulfate chains of syndecan-1 by heparinase is associated with increased syndecan-1 shedding, MMP-9 and VEGF expression, and elevated angiogenesis, events that may also fuel osteolysis.(16–18) This is consistent with a reported positive correlation between MMP-9 and VEGF levels and bone lesion score in myeloma patients.(19)


Myeloma bone disease.

Sanderson RD, Epstein J - J. Bone Miner. Res. (2009)

Mechanisms of myeloma-mediated bone destruction. The cartoon depicts a myeloma lesion and the events that occur, leading to formation of an osteolytic lesion. (1) Myeloma cells secrete DKK1 and FRP2 that inhibit Wnt pathway signaling, thus blocking osteoblastogenesis. (2) RANKL (blue triangles) expression on the surface of osteoblasts and bone marrow stromal cells is elevated, and expression of OPG (orange circles) is suppressed. In addition, OPG binds to syndecan-1 on the surface of myeloma cells and is internalized and degraded further shifting the balance toward osteoclastogenesis. (3) Myeloma cells express high levels of either cell surface or soluble RANKL. (4) The high levels of RANKL in the lesion lead to hyperstimulation of myeloid precursor differentiation into osteoclasts. Once mature, the osteoclasts degrade bone and release factors (green triangles) that stimulate myeloma growth. The net effect of these processes is extensive loss of bone at sites of myeloma foci leading to radiologically identifiable osteolytic lesions as shown in the X-ray on the right (arrow points to lesion).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3276340&req=5

fig01: Mechanisms of myeloma-mediated bone destruction. The cartoon depicts a myeloma lesion and the events that occur, leading to formation of an osteolytic lesion. (1) Myeloma cells secrete DKK1 and FRP2 that inhibit Wnt pathway signaling, thus blocking osteoblastogenesis. (2) RANKL (blue triangles) expression on the surface of osteoblasts and bone marrow stromal cells is elevated, and expression of OPG (orange circles) is suppressed. In addition, OPG binds to syndecan-1 on the surface of myeloma cells and is internalized and degraded further shifting the balance toward osteoclastogenesis. (3) Myeloma cells express high levels of either cell surface or soluble RANKL. (4) The high levels of RANKL in the lesion lead to hyperstimulation of myeloid precursor differentiation into osteoclasts. Once mature, the osteoclasts degrade bone and release factors (green triangles) that stimulate myeloma growth. The net effect of these processes is extensive loss of bone at sites of myeloma foci leading to radiologically identifiable osteolytic lesions as shown in the X-ray on the right (arrow points to lesion).
Mentions: In myeloma, osteoclasts are hyperstimulated predominantly because of dysregulation of three TNF family members: RANK, its ligand (RANKL), and osteoprotegerin (OPG). The binding of RANKL to RANK that is present on the surface of myeloid precursors is needed for differentiation of the precursors into osteoclasts. The activation of RANK is antagonized when soluble OPG binds to RANKL, thereby preventing RANKL activation of RANK. This dampens the rate of osteoclastogenesis. In normal bone, the RANK/RANKL/OPG system works in concert to balance bone turnover and maintain normal homeostasis. In myeloma, both the tumor cells and the bone marrow stromal cells can produce osteoclast-activating factors, thereby shifting the balance toward enhanced osteoclastogenesis and bone destruction. This often occurs within the local tumor microenvironment where osteoclast numbers are seen to be elevated in areas adjacent to myeloma tumor cells. RANKL production is elevated in the bone marrow stroma in myeloma, and in addition, the tumor cells can also express RANKL(8–13) (Fig. 1). High expression levels of membrane-associated RANKL on myeloma cells has been correlated with the presence of multiple bone lesions in myeloma patients.(12,13) In addition, the membrane form of RANKL can be released by proteases. This released, soluble form of RANKL can diffuse away from the local tumor environment to promote widespread osteoclast activation, thereby contributing to systemic bone loss in myeloma.(14) Interestingly, although myeloma cells do not produce OPG, they can diminish the effect that OPG has on inhibiting osteoclastogenesis. This occurs when the heparan sulfate proteoglycan syndecan-1 on the surface of myeloma cells binds to OPG, leading to internalization and degradation of the OPG.(15) Because syndecan-1 is expressed at high levels on most myeloma tumor cells, the binding and degradation of OPG may be a substantial contributor to the bone-degrading phenotype of myeloma. Moreover, clipping of the heparan sulfate chains of syndecan-1 by heparinase is associated with increased syndecan-1 shedding, MMP-9 and VEGF expression, and elevated angiogenesis, events that may also fuel osteolysis.(16–18) This is consistent with a reported positive correlation between MMP-9 and VEGF levels and bone lesion score in myeloma patients.(19)

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sanderson@uab.edu

ABSTRACT

Bone disease is a characteristic feature of myeloma and causes devastating side effects that impact patient quality of life and survival. New findings over the last several years have led to a better understanding of the molecular mechanisms regulating bone disease including the understanding that myeloma bone disease results from hyperstimulation of osteoclastogenesis and inhibition of osteoblastogenesis. From these mechanistic findings, promising new therapies including bortezomib and denosumab have evolved and give hope for lessening the impact of osteolytic bone disease in myeloma. New therapies such as anti-DKK1 antibodies are on the horizon. Despite these advances, lingering questions remain that need to be addressed. Why in a small minority of patients do osteoblasts near tumor foci continue to survive and proliferate, whereas in most patients osteoblastogenesis is inhibited? Can combinations of bone preserving and bone forming therapies lead to repair of osteolytic lesions in myeloma? To what extent do myeloma tumor cells exhibit direct osteolytic effects separate from osteoclasts, and how can these effects be diminished? Tackling these and other remaining mechanistic questions will lead to even better therapeutic approaches to controlling myeloma bone disease.

Show MeSH
Related in: MedlinePlus