The effect of zoledronic acid on the function and differentiation of myeloid cells

Abstract

BACKGROUND AND OBJECTIVES: Bisphosphonates are widely used for treatment of osteoporosis and metastases of the skeletal system. Recent data suggest that bisphosphonates may not only reduce bone loss but also exert direct anti-tumor, anti-angiogenic and E inverted exclamation markE not T-cell activating effects, properties which depend at least partially on their affinity to phagocytosing and antigen-presenting cells (i.e. osteoclasts and monocytes). The latter represent the major source of dendritic cells (DC). Thus, we determined the immunomodulatory properties of zoledronic acid (ZA), a member of the latest generation of bisphosphonates. DESIGN AND METHODS: Primary human monocytes, macrophages, immature and mature dendritic cells were incubated with increasing doses of ZA for subsequent analysis of cell surface marker expression and cytokine production. In addition, phagocytic and allo-stimulatory properties, differentiation capacity, and NF-kB activation were determined. RESULTS: Therapeutic doses of ZA inhibited the in vitro generation of DC from monocytes, as shown by an impaired up-regulation of maturation markers. In parallel, ZA also impaired lipopolysaccharide-induced activation of NF-kB, which represents a critical factor for DC differentiation. Accordingly, the activation of allogeneic T cells by ZA-treated DC in a mixed-lymphocyte reaction was significantly reduced. Finally, ZA inhibited the production of tumor necrosis factor-a in monocyte-derived cells and impaired the phagocytic capacity of macrophages and immature DC. INTERPRETATION AND CONCLUSIONS: Therapeutic doses of ZA modulate monocyte, macrophage and DC function and might thereby modulate immune function.