Advances in the understanding of myeloma bone disease and tumour growth

Abstract

Advances in multiple myeloma support the notion that the associated bone disease, characterized by increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and necessity of tumour progression. Osteoblastogenesis is suppressed by secreted inhibitors and dysregulation of cell-surface 'coupling' factors on osteogenic cells. Osteoclastogenesis is increased as a consequence of osteoblast deactivation and of production of osteoclast-activating factors. Osteoclasts express soluble and cell-surface factors that stimulate myeloma growth, while osteoblasts produce bone-building factors that restrain growth of myeloma cells that are dependent on the microenvironment; detailed molecular mechanisms are discussed. Experimental and clinical findings indicate that pharmacological and experimental osteoblast-activating agents that effectively promote bone formation also reduce growth of myeloma cells within bone, seemingly by simultaneously stimulating osteoblastogenesis and restraining osteoclastogenesis. Unravelling mechanisms of myeloma bone disease expands horizons for developing novel interventions and also facilitates better understanding of the association between induction of osteolysis and disease progression.

Figure 1

Main cellular and molecular factors associated with MM-induced bone disease. Osteolytic lesions are induced by uncoupling of bone metabolism, resulting in increased bone resorption by osteoclasts and reduced bone formation by osteoblasts. Interactions between MM cells and various BM cells (e.g., osteoblast and osteoblast precursors, activated T lymphocytes, dendritic cells) result in increased production of osteoclast-activating factors (e.g., RANKL, IL-3, MIP1α) and/or osteoblast-inactivating factors (e.g., DKK1, sFRP2, IL-7). OPG levels in lytic lesions are low as a consequence of reduced osteoblast numbers and of OPG internalization and degradation by MM cells in a mechanism mediated by binding to syndecan-1 on MM cell surfaces. Syndecan-1 molecules shed from MM cells also bind and localize factors such as HGF that act on bone cells to promote osteolysis. Osteoblastogenesis is impaired by cell–cell contact mediated by VCAM-1 on MM cells and VLA-4 on osteoblast precursors and also by dysregulation of cell-surface coupling factors such as ephrinB2 and EphB4 on osteoblast precursors. Osteoclasts may form by MM cells fusing together or by dendritic cells fusing with osteoclast precursors, contributing to increased numbers of osteoclasts. Other cellular elements of BM, such as megakaryocytes, macrophages, and Th17 T lymphocytes, may also be cultivated by MM to promote bone disease (see text for details).

Figure 2

Roles of bone cells in myeloma cell survival and growth. In focal/lytic lesions, osteoclasts and mesenchymal cells (e.g., MSCs) are cultivated by myeloma cells to express tumour-promoting factors (e.g., FAP) and produce MM growth factors (e.g., osteopontin, IL-6), which induce survival signalling and promote dedifferentiation of myeloma cells into an immature, apoptosis-resistant phenotype. In contrast, bone-building osteoblasts may inhibit myeloma cell growth by producing bone-building products, including some SLRPs. Agents that suppress osteoclast activity and/or stimulate osteoblastogenesis help re-establish balanced bone remodeling and contribute to controlling MM (see text for details); these agents include bortezomib, anti-DKK1, Wnt-activators, bisphosphonates, IMiDs, and anti-RANKL.