Abstract
Multiple myeloma, a cancer of plasma cells, is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent metabolic complication of myeloma in patients, and excessive osteolysis plays a major contributory role in its pathogenesis. The clinical presentation of hypercalcemia in patients varies depending on the level of ionized calcium; it can be life threatening, as in the case of hypercalcemic crisis, requiring immediate medical treatment to prevent death. During the past few years there have been exciting developments in our understanding of the pathogenesis of myeloma bone disease; in particular, key mediators of the osteoclastic bone resorption in myeloma have been identified, including receptor activator of nuclear factor-κB ligand (RANKL) and macrophage inflammatory protein-1α. There is also increasing evidence that Dickkopf 1, which has been shown to be over-expressed in myeloma patients, is also a potent stimulator of osteoclast formation and activity. Importantly, the available data suggest that RANKL is the final common mediator of osteoclastic bone resorption, irrespective of the upstream initiator molecule. This brief review presents an overview of the roles played by these mediators in inducing osteolysis in myeloma bone disease, and it discusses targeting RANKL as a potential new treatment strategy in myeloma bone disease and myeloma-associated hypercalcemia.
Highlights
Multiple myeloma, a clonal neoplasm of plasma cells, is the second most common adult hematologic malignancy, and it is the most common cancer with skeleton as its primary site
The primary cause of the hypercalcemia is widespread tumor-induced bone destruction. This is primarily due to increased osteoclastic bone resorption caused by potent cytokines expressed or secreted locally by the myeloma cells or over-expressed by other cells in the local microenvironment [1]
Given the recently discovered role of canonical Wnt signaling in osteoclast formation and the osteoclastogenic effect of DKK1, further insights into the mechanisms involved in modulating the effects of DKK1 in myeloma bone disease will help to define other novel molecular targets, facilitating development of new therapies for the treatment of associated hypercalcemia
Summary
A clonal neoplasm of plasma cells, is the second most common adult hematologic malignancy, and it is the most common cancer with skeleton as its primary site. The primary cause of the hypercalcemia is widespread tumor-induced bone destruction This is primarily due to increased osteoclastic bone resorption caused by potent cytokines expressed or secreted locally by the myeloma cells (receptor activator of nuclear factor-κB ligand [RANKL], macrophage inflammatory protein [MIP]-1α, and tumor necrosis factors [TNFs]; see below) or over-expressed by other cells in the local microenvironment [1]. Canonical Wnt signaling was recently shown to modulate RANKL and OPG expression in osteoblasts in vitro, resulting in inhibition of osteoclastogenesis [34] Consistent with these observations, it was recently reported that DKK1 enhances osteoclast formation and bone resorption in vitro [35], and systemic administration of antiDKK1 antibodies was shown to block osteoclast formation in vivo in a murine model of myeloma bone disease [36]. Given the recently discovered role of canonical Wnt signaling in osteoclast formation and the osteoclastogenic effect of DKK1, further insights into the mechanisms involved in modulating the effects of DKK1 in myeloma bone disease will help to define other novel molecular targets, facilitating development of new therapies for the treatment of associated hypercalcemia
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