Research in Sheffield
Staff
Our current research into multiple myeloma and its associated bone disease is undertaken in the Division of Biochemical and Musculoskeletal Medicine within the University of Sheffield Medical School. Staff involved in these projects include Dr Peter Croucher, Dr Claire Shipman, Dr Ingunn Holen and a number of research technicians and graduate students.
Introduction
One of the most important clinical features of multiple myeloma is the development of osteolytic bone disease which predominantly affects the skull, ribs, vertebrae, pelvis and proximal long bones. Many patients have pathological fractures at diagnosis with some studies reporting that more than 50% of patients present with vertebral fractures and up to 30% of patients with non-vertebral fractures. Although the osteolytic bone disease is a major cause of morbidity in patients with multiple myeloma, our understanding of the mechanism of bone loss and the agents that mediate this aspect of the disease remains incomplete. The major focus of research in Sheffield is to improve our understanding of the mechanisms of bone loss in patients with multiple myeloma and to identify therapeutic approaches to managing this aspect of the disease.
The role of local growth factors and cytokines
A number of cytokines have been implicated in the pathogenesis of myeloma bone disease although the identity of the factors involved in patients with myeloma has yet to be established. We are currently attempting to determine the role of two families of molecules in the development of both the bone disease and the myeloma disease itself. These systems include:-
1. The interleukin-6 / interleukin-6 receptor system
Interleukin-6 (IL-6) is a major growth and survival factor for myeloma cells and may also play a role in the development of the bone disease. IL-6 elicits its effect by binding to the IL-6 receptor (IL-6R) which then associates with a second, signal transducing, molecule known as gp130, which leads to the transduction of a signal to the cell. A soluble form of the IL-6R (sIL-6R) has been identified which is unusual amongst soluble cytokine receptors in that it retains biological activity and acts as an agonist by binding IL-6, associating with gp130 and allowing signal transduction. In patients with multiple myeloma serum concentrations of the sIL-6R are increased and may be associated with poor prognosis. We are currently determining how the sIL-6R is generated in myeloma cells and the implications of blocking this process on both the proliferation and survival of tumour cells and the development of the bone disease.
2. The osteoprotegerin ligand system
A number of recent studies have demonstrated that the osteoprotegerin ligand (OPGL) system plays a critical role in osteoclast development. OPGL is expressed by bone marrow stromal cells or osteoblasts and interacts with a receptor on osteoclast precursors to promote the differentiation of these cells into functional osteoclasts. The system is inhibited by a soluble decoy receptor known as osteoprotegerin. Since this system plays an important role in the normal development of osteoclasts it is likely that it may also be altered by interactions with myeloma cells. We are currently investigating the role of this system in the development of myeloma bone disease.
The role of proteinases
Proteinase play an important role in numerous biological processes. We have shown that a member of the metalloproteinase family is important in the release of the IL-6R from human myeloma cells, although the identity of this proteinase remains unclear. Our studies have shown that human myeloma cells express members of a new family of proteinases known as the ADAM (A Disintegrin and Metalloproteinase) family and that they are likely to be responsible for shedding of the IL-6R. We are now trying to identify which members of this family are responsible for this event in myeloma cells. In addition, we are also investigating the effects of proteinase inhibitors on the development of myeloma and the associated bone disease.
The role of bisphosphonates
Bisphosphonates are potent inhibitors of bone resorption. Recent studies have suggested that they may be effective in the management of myeloma bone disease. In addition, there are data to suggest that these drugs may also have positive effects on other aspects of the disease. These observations may reflect either direct effects on the myeloma cells themselves or indirect effects via an inhibition of bone resorption. We are currently investigating whether bisphosphonates can directly modulate the behaviour of myeloma cells in vitro and in vivo.