Abstracts of 2nd Scientific Meeting on Bone Disease in Multiple Myeloma
Mechanisms of Bone Loss in Myeloma
G.R. Mundy, B. Oyajobi., University of Texas Health Science Center, San Antonio, Texas, USA
Myeloma is characterized by an incapacitating bone disease which affects the majority of patients. We have investigated the pathophysiology and novel treatment approaches for this bone disease using an in vivo murine model which arises spontaneously in mice, and is associated with the subsequent bone diseasewhich mimics the human condition. We have found using this model that bisphosphonates inhibit osteolytic bone disease, but have no effect on tumor burden. We have also examined other potential inhibitors of the bone destruction that occurs in myeloma, and have identified several novel approaches to the treatment of myeloma bone disease. Among these are the use of specific antagonists to RANK ligand. We have found that cell-cell interactions between myeloma cells and stromal cells in the bone microenvironment enhance production of RANK ligand and a number of other cytokines by both myeloma cells and stromal cells, and which stimulate bone resorption. These other cytokines include interleukin-1, tumour necrosis factor b and MIP1a. We have found that a chimeric antagonist to RANK ligand known as RANKFc inhibits the myeloma bone disease in vivo and also reduces tumor burden. We have also examined specific antagonists of the cell-cell interactions which are responsible for enhanced production of these cytokines, including a4b1 integrin and VCAM-1. Neutralizing antibodies to these cell attachment molecules also reduce the bone lesions and the extent of myeloma burden. More recently, we have examined the role of the proteasome in the pathophysiology of myeloma bone disease. We have found that specific antagonists of the chymotrypsin-like activity of the multimeric proteasome have a powerful effect to reduce myeloma burden and subsequent lesions. Since myeloma is a diseasewhich is uniformly fatal and is badly in need of improved methods of treatment, we are hopeful that these novel approaches to both the underlying malignancy as wellas the subsequent bone disease will lead to therapies in patients confirmed in later clinical studies.