Molecular and cellular studies of zoledronic acid : a potent inhibitor of multiple myeloma-induced osteolysis

Abstract

Myelomatosis (MM) is an incurable B cell malignancy, characterised by the presence of osteolytic bone lesions, a major cause of morbidity and mortality. This study investigated the effect of zoledronic acid, a potent nitrogen-containing bisphosphonate (BP), on myeloma cells and osteoblasts-like cells to establish the molecular and cellular mechanism responsible for the clinical effectiveness of BPs in the treatment of patients with MM. These studies indicate that zoledronic acid induces apoptotic and non-apoptotic cell death in myeloma cell lines bV (1) inducing S phase arrest in a time and dose dependent manner, (2) inhibiting the mevalonate pathway, and (3) up regulating TRAIL expression and uncoupling the regulated expression of TRAIL death and decoy receptors. Using an established model of osteoblast differentiation, zoledronic acid was found to increase the number of mature osteoblast/osteocyte-like cells, with a concomitant decrease in the number of stromal precursor cells. In accordance with these findings, zoledronic acid was found to enhance the osteoblast-like cells' ability to form a mineralised bone matrix, when used at concentrations in the range of 5pM and 25 pM. Therefore, we conclude that zoledronic acid mediates the differentiation of osteoblasts-like cells, which accounts for the enhanced bone formation. Zoledronic acid also upregulates the gene expression of IL-l8 and TNF-cr, which serve to increase the number of osteoprogenitors cells which in tum can respond to zoledronic acid. Furthermore, zoledronic acid was found to decrease the expression of membrane-associated RANKL by increasing TACE expression, a metalloproteinase disintegrin. In conclusion, the studies presented herein show that zoledronic acid enhances bone formation by directly acling on osteoblasts. In conclusion, work reported in this thesis suggests that myeloma cell death, and proliferation and maturation of osteoblasts represent two mechanisms that zoledronic acid inhibits MMinduced ostolysis.