Pathogenesis of bone disease in multiple myeloma: from bench to bedside

Abstract

Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. During the last years, osteocytes have emerged as key regulators of bone loss in myeloma through direct interactions with the myeloma cells. The myeloma-induced crosstalk among the molecular pathways establishes a positive feedback that sustains myeloma cell survival and continuous bone destruction, even when a plateau phase of the disease has been achieved. Targeted therapies, based on the better knowledge of the biology, constitute a promising approach in the management of myeloma-related bone disease and several novel agents are currently under investigation. Herein, we provide an insight into the underlying pathogenesis of bone disease and discuss possible directions for future studies.

Fig. 1. Schematic overview of myeloma-related bone disease

The intercellular interactions between BMSCs and MM cells along with the involvement of immune cells, such as Th17 cells, induce cytokine release (IL-1b, IL-3, IL-6, IL-11, IL-17) and secretion of pro-osteoclastogenic factors such as TNF-α, CCL-3, SDF-1α, and annexin II in the bone marrow microenvironment. These cytokines promote increased osteoclast activity and inhibit osteoblastogenesis. Adhesion molecules such as VCAM-1 on BMSCs and VLA-4 on MM cells mediate cell-to-cell contact. Notch, expressed by MM cells, binds to Jagged, expressed by neighboring MM cells and BMSCs, and activate intracellular cascades favoring RANKL production. MM cells also enhance the apoptosis of osteocytes that also release RANKL. RANKL binds directly to RANK on osteoclast precursors and promotes osteoclastogenesis. Syndecan-1 on MM cells binds and inactivates OPG, the RANKL soluble decoy receptor. Osteoclasts also produce factors sustaining MM cell growth and survival, including IL-6 and BAFF. Furthermore, MM cells produce soluble factors that inhibit osteoblastogenesis such as DKK1, sFRP-2, and sclerostin. Activin-A secreted by BMSCs also impedes osteoblast production, while at the same time activates osteoclasts. EphB4 on osteoblasts and BMSCs binds to EphrinB2 on osteoclasts and results in bidirectional signaling that ultimately induces osteoclastogenesis and impedes osteoblastogenesis. All these interactions lead to increased osteoclast activity, diminished osteoblast function, increased bone resorption, bone destruction and development of osteolytic lesions, and/or pathological fractures