Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast

Abstract

Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e., any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast.

Keywords: Bone; Multiple myeloma; Osteoblasts.

Figure 1. The osteoblast as a central mediator of multiple myeloma growth

Multiple Myeloma is a disease of the plasma cell. Multiple myeloma tumor cells grow within the bone microenvironment. Increasing evidence shows that osteoblasts play a central role in regulating the growth of multiple myeloma in the bone marrow through direct interactions or influences on other bone marrow niche cells. Within the bone microenvironment (left), osteoblasts secrete factors such as decorin (A) that directly lead to myeloma cell apoptosis and cell cycle arrest. In a reciprocal interaction, myeloma cells suppress osteoblast generation via DKK1. In addition, osteoblasts recruit immune cells to the bone marrow (B) where they can have anti-tumor effects, although recruitment of regulatory T-cells and myeloid derived suppressor cells can promote myeloma growth by inhibiting the anti-tumor immune response. C) Increased osteoblastic activity leads to increased osteoclast activity, which can promote the survival and proliferation of myeloma cells. In turn, myeloma cells increase osteoclastic activity. D) The mesenchymal stem cell within the marrow niche can have direct positive effects on myeloma cells, and also determines the balance of resident osteoblasts and adipocytes. E) The contribution of marrow adipocytes is still under active investigation, but marrow adipocytes may suppress normal hematopoiesis, leading to the development of myeloma cells. Other systemic influences (right) include adipose tissue, which, under conditions of excess adipocyte accumulation, induces systemic inflammation and release of adipokines and estrogen that may promote myeloma growth and survival.