Chapter 6 – Bone disease

Contributor: Evangelos Terpos

2 – Biology of multiple myeloma bone disease

The development of bone disease is related to an uncoupled bone remodeling: the increased osteoclast-mediated bone resorption is accompanied by a reduction in new bone formation. Factors produced by myeloma cells stimulate osteoclasts to resorb bone and inhibit osteoblast activity. In turn, growth factors released by the increased bone resorptive process, also increase the growth of MM cells, creating a vicious cycle of tumour expansion and bone destruction (Figure 6.1).

The biologic pathway of the receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL), and osteoprotegerin (OPG), which is the decoy receptor of RANKL, is of major importance for the increased

Figure 6.1 Biology of bone disease.

BAFF, B-cell activating factor; bALP, bone specific alkaline phosphatase; bFGF, basic fibroblast growth factor; CCL3, CC chemokine ligand 3; CD138, syndecan 1; CTX, C-terminal cross-linking telopeptide of type-1 collagen; DKK-1, dickkopf-1; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule 1; ICTP, C-terminal cross-linking telopeptide of type-1 collagen generated by metalloproteinase; IL-1β/6, interleukin 1β/6; M-CSF, macrophage colony-stimulating factor; MM, multiple myeloma; NTX, N-terminal cross-linking telopeptide of type-1 collagen; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-kappa B ligand; TNFα, tumor necrosis factor α; TRACP-5b, tartrate-resistant acid phosphatase isoform 5b; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor. Reproduced with permission from © Nature Publishing Group, 2013. All rights reserved. Terpos and Christoulas [2].

osteoclast activity observed in MM [3]. Myeloma cells adhere to bone marrow stromal cells (BMSCs) through binding of very late antigen 4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1) – present on the surface of MM cells – to vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), respectively, which are expressed on stromal cells. The adherence of MM cells to BMSCs enhances the production of RANKL and other cytokines with osteoclast-activating function activity (interleukin 6 [IL-6], IL-11, IL-1b, tumor necrosis factors [TNFs], and basic fibroblast growth factor [bFGF]), while it suppresses the production of OPG – the decoy receptor of RANKL. Furthermore, myeloma cells produce factors such as CC chemokine ligand 3 (CCL3), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) that enhance the proliferation and differentiation of osteoclast precursors. Myeloma cells may express RANKL, while syndecan 1 (CD138) expressed on the surface of, and secreted from, the myeloma cells can bind soluble OPG, thus preventing its inhibitory effect on RANKL function. Activin A has also been implicated in MM bone disease, through stimulating RANK expression and inducing osteoclastogenesis [4,5]. Therefore, the ratio of RANKL/OPG is increased, leading to osteoclast differentiation, proliferation and activation, and to increased bone resorption, as is reflected by the increased levels of bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b], N-terminal cross-linking telopeptide of type-1 collagen [NTX], C-terminal cross-linking telopeptide of type-1 collagen generated by metalloproteinase [ICTP], and C-terminal cross-linking telopeptide of type-1 collagen [CTX]).

The production of VEGF, bFGF, and HGF by MM cells and BMSCs results in increased angiogenesis and in turn, IL-6 produced by osteoclasts, endothelial cells, and BMSCs increases the growth of MM cells. However, Wnt signaling inhibitors, such as dickkopf-1 (DKK-1) and sclerostin, produced by MM cells and osteocytes in apoptosis, respectively [6–8], disrupt osteoblast maturation and function, with reduced formation of new bone, reflected by decreased levels of bone formation markers (bone specific alkaline phosphatase [bALP] and osteocalcin [OC]). The net result of all these complex interactions is tumor expansion and osteolytic bone disease. As these molecules also interfere with tumor growth and survival, they provide possible targets for the development of novel drugs for the management of lytic disease in myeloma.