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Fall 1999 Volume 3, Issue 6:
The Role Of Cell-Cell Interactions In The Development Of Osteolytic Bone Lesions In Myeloma
By Babatunde O. Oyajobi, MBBCh, PhD, Univ. Of Texas
10.01.99
Overview by Prof. Brian G. M. Durie

Why do myeloma patients develop severe bone damage and how can it be stopped or prevented? These are critical issues for many patients in need of better treatment options. Even though bisphosphonates are very helpful, bone problems are still threatening for those with progressive and/or chemotherapy-resistant disease. The research project by Dr. Oyajobi looks at novel ways to block the activation of the osteoclast, the cell responsible for myeloma bone damage. Blocking a newly recognized substance called RANK ligand and the binding or adhesion between myeloma cells and osteoclasts will be evaluated. If the blocking proves to be efficient and specific for myeloma induced bone disease without interfering with normal bone metabolism, new treatments may emerge from these studies. We wish our grant recipient the best of success.

THE ROLE OF CELL-CELL INTERACTIONS IN THE DEVELOPMENT OF OSTEOLYTIC BONE LESIONS IN MYELOMA
by Babatunde O. Oyajobi, MBBCh, PhD Univ. of Texas Health Science Center

Myeloma is unique amongst the hematologic malignancies in its propensity to cause extensive bone destruction. This progressive bone destruction manifests as intractable bone pain, spontaneous fractures, nerve compression syndromes, life-threatening hypercalcemia and a markedly reduced quality of life. Although the bone destruction is due to increased osteoclast (Ocl) activity, the precise nature and source of the bone-resorbing cytokines that are invovled have not been identified. In most patients, the myeloma cells exist as "nests" in close apposition to osteolytic lesions suggesting that autocrine, paracrine and/or juxtacrine mechanisms are involved. There appears to be a complicated but unique relationship between myeloma and Ocl. Although myeloma cells stimulate Ocl formation in vivo, it remains unclear whether the tumor cells themselves produce factor(s) that can directly stimulate Ocl formation since neither human nor murine myeloma cells which cause extensive bone resorption in vivo, produce significant amounts of bone-resorbing activity in vitro. Thus, the nature of the relationship between myeloma cells and Ocl remains unresolved.

In the last year, there have been important observations that have clarified the mechanisms by which osteoclasts are formed and activated. The transcription factor, nuclear factor kappa B (NF-KB), has been observed by our group (Franzoso et al., 1997) to be essential for Ocl formation. More recent studies have suggested that Receptor Activator of NF-KB (RANK), the receptor which activates NF-KB, is present on osteoclast precursors. Furthermore, RANK ligand (RANKL), a novel member of TNF ligand superfamily, has been shown to be indispensible for Ocl formation and activation both in vitro and in vivo. Collectively, the study strongly indicate that RANKL is unique as it may be the final common mediator for the osteoclastogenic effect of other cytokines and hormones such as tumor necrosis factor ß (TNFß), TNFa, interleukin (IL)-1, IL-6, leukemia inhibitory factor (LIF), parathyroid hormone-related peptide (PTHrP) and 1,25(OH)2D3. We have recently found that murine myeloma (5TGM1) cells and the murine bone marrow stromal cell line, ST2 do not express RANKL when cultured separately. However, RANKL expression was strongly induced in co-cultures of 5TGM1 and ST2 cells. This interaction is mediated by vascular cell adhesion molecule-1 (VCAM-1) on the ST2 cells and a4ß1 integrin on the myeloma cells. Treatment of 5TGM1 cells with a recombinant soluble form of VCAM-1 (rsVCAM-1), which acts as a functional ligand for a4ß1, also induced RANKL expression in the myeloma cells independent of ST2 cells. Furthermore, conditioned media from myeloma cells treated with rsVCAM-1 and from the myeloma cell/stromal cell co-culture induced RANKL expression in fresh cultures of ST2 cells. Taken together, these data raise the possibility that in myeloma, physical interactions between the cell adhesion molecules expressed on the surface of the myeloma cells and their ligands in the bone microenvironment play a critical role in initiating the sequence of events that result in the characteristic bone destruction. Based on these observations, we hypothesize that: (1) Aberrant expression of RANKL in the bone microenvironment in myeloma plays a role in the increase osteoclastogenesis that results in bone destruction; and (2) Cell-cell interactions mediated via VCAM-1/a4ß1 binding are a prerequisite for the increased Ocl formation.

Our group has developed and characterized a murine model of human myeloma bone disease in which 5TGM1 cells (or other myeloma cells from the 5T series) injected into tail veins of syngeneic C57BL/LaKwRij mice reliably cause osteolytic bone lesions which are visible radiologically and can be confirmed histologically. We plan to use this model to test the above hypotheses. Specifically, we plan to investigate the role of cell-cell interaction in the growth of myeloma in bone as well as in the development and progression of osteolytic lesions. Our approach will be to disrupt VCAM-1/a4ß1 binding in vivo using well characterized neutralizing antibody to VCAM-1. In addition, we will determine the role that tumor and/or stromal cell-induced RANKL plays in myeloma bone disease in vivo using recombinant soluble RANK fusion protein to block the interaction of RANKL with endogenuous RANK on Ocl progenitors.

The interaction between the tumor cells and marrow stroma facilitates the growth and survival of myeloma in bone. Since the sequence of events that result in bone destruction may also depend on this interaction, a better understanding of the process and its functional consequences will offer opportunities for novel and specific therapeutic intervention. We anticipate that the proposed studies will indicate whether therapeutic agents designed to disrupt VCAM-1/a4ß1 binding or to block RANK activation will provide effective therapy against bone destruction in myeloma.


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