Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1-integrin enhances production of osteoclast-stimulating activity

Abstract

Myeloma is a unique hematologic malignancy that exclusively homes in the bone marrow and induces massive osteoclastic bone destruction presumably by producing cytokines that promote the differentiation of the hematopoietic progenitors to osteoclasts (osteoclastogenesis). It is recognized that neighboring bone marrow stromal cells influence the expression of the malignant phenotype in myeloma cells. This study examined the role of the interactions between myeloma cells and neighboring stromal cells in the production of osteoclastogenic factors to elucidate the mechanism underlying extensive osteoclastic bone destruction. A murine myeloma cell line 5TGM1, which causes severe osteolysis, expresses α4β1-integrin and tightly adheres to the mouse marrow stromal cell line ST2, which expresses the vascular cell adhesion molecule-1 (VCAM-1), a ligand for α4β1-integrin. Co-cultures of 5TGM1 with primary bone marrow cells generated tartrate-resistant acid phosphatase-positive multinucleated bone-resorbing osteoclasts. Co-cultures of 5TGM1 with ST2 showed increased production of bone-resorbing activity and neutralizing antibodies against VCAM-1 or α4β1-integrin inhibited this. The 5TGM1 cells contacting recombinant VCAM-1 produced increased osteoclastogenic and bone-resorbing activity. The activity was not blocked by the neutralizing antibody to known osteoclastogenic cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor, or parathyroid hormone-related peptide. These data suggest that myeloma cells are responsible for producing osteoclastogenic activity and that establishment of direct contact with marrow stromal cells via α4β1-integrin/VCAM-1 increases the production of this activity by myeloma cells. They also suggest that the presence of stromal cells may provide a microenvironment that allows exclusive colonization of myeloma cells in the bone marrow.

The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications

“…In previous studies, VLA-4-VCAM-1 interaction also triggered enhanced osteoclastogenic activity, thereby inducing bone destruction (Michigami et al, 2000;Abe et al, 2009). Based on these findings, our ongoing studies are evaluating a role for Natalizumab in ameliorating MM bone disease.…”

Targeting Multiple Myeloma Cells and Their Bone Marrow Microenvironment

“…Another important adhesion molecule involved in myeloma bone disease is the α v β 3 integrin. 16 This integrin is expressed on myeloma tumor cells, and its interaction with the vascular cell adhesion molecule (VCAM-1) present on BM SCs increases osteoclastogenesis and bone resorbing activity.…”

Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease

“…. Malignant plasma cells are apparently engaged in the deregulation of bone resorption by inducing stromal cells to secrete a number of osteoclast activating factors, such as interleukin 1b (IL-1b), IL-6 and tumour necrosis factor (TNF)-b (Michigami et al, 2000). These cytokines stimulate osteoblasts to enhance the production of trans-membranous RANKL [receptor activator of nuclear factor (NF)-kB ligand] (Lacey et al, 1998;Yasuda et al, 1998), a major osteoclastogenic factor that may also be directly secreted by myeloma cells (Oyajobi et al, 1998).…”