Cellular mechanisms of multiple myeloma bone disease

Abstract

Multiple myeloma (MM) is a hematologic malignancy of differentiated plasma cells that accumulates and proliferates in the bone marrow. MM patients often develop bone disease that results in severe bone pain, osteolytic lesions, and pathologic fractures. These skeletal complications have not only a negative impact on quality of life but also a possible effect in overall survival. MM osteolytic bone lesions arise from the altered bone remodeling due to both increased osteoclast activation and decreased osteoblast differentiation. A dysregulated production of numerous cytokines that can contribute to the uncoupling of bone cell activity is well documented in the bone marrow microenvironment of MM patients. These molecules are produced not only by malignant plasma cells, that directly contribute to MM bone disease, but also by bone, immune, and stromal cells interacting with each other in the bone microenvironment. This review focuses on the current knowledge of MM bone disease biology, with particular regard on the role of bone and immune cells in producing cytokines critical for malignant plasma cell proliferation as well as in osteolysis development. Therefore, the understanding of MM pathogenesis could be useful to the discovery of novel agents that will be able to both restore bone remodelling and reduce tumor burden.

Figure 1

Interaction between bone cells and bone marrow microenvironment cells in promoting both malignant plasma cell survival and bone lesions in MM patients. Myeloma cells can directly support osteoclast formation and activity as well as inhibit osteoblast differentiation by releasing numerous cytokines. Moreover, other molecules can be secreted by bone cells and other cells interacting with each other in the bone microenvironment, thus supporting both the progression of MM tumor burden and the development of MM bone disease.