Osteoclast-gain-of-function promotes tumor growth in bone

CXCR4 regulates hematopoietic and tumor cell homing to bone and plays a role in lymphopoeisis and myelopoiesis. Since at least one myeloid cell, the osteoclast, affects tumor growth within bone, we investigated the role of CXCR4 in osteoclastogenesis and bone metastasis. CXCR4 hematopoietic null mice exhibited elevated markers of bone resorption and increased osteoclast perimeter along bone compared to controls. Loss of CXCR4 accelerated osteoclastogenesis and enhanced bone resorption in vitro. CXCR4 activation impaired RANKL-mediated phosphorylation of p38 MAPK, an important molecule in osteoclast differentiation. Finally, bone, but not subcutaneous or lung, tumor growth was significantly increased in CXCR4 hematopoietic null mice compared to controls by in vivo bioluminescence imaging and histologie analysis. These data demonstrate that CXCR4 negatively regulates osteoclastogenesis and disruption of CXCR4 on hematopoietic cells enhances skeletal tumor burden. Therefore, caution should be taken when considering use of CXCR4 inhibitors to prevent metastasis.;One pharmacologie agent that disrupts the SDF-1/CXCR4 chemokine axis and is commonly used in cancer patients is granulocyte colony-stimulating factor (G-CSF). G-CSF is used to treat chemotherapy-induced neutropenia, but is also associated with decreased bone minerai density (BMD). We used G-CSF as a tool to investigate the impact of increased OC activity on tumor growth in two murine osteolytic tumor models. An eight-day course of G-CSF significantly decreased BMD and increased OC perimeter along bone. Mice administered G-CSF demonstrated significantly increased tumor growth in bone by in vivo bioluminescence imaging and histologie analysis. However, osteoclast defective osteoprotegerin transgenic (OPGTg) mice and bisphosphonate-treated mice were resistant to the effects of G-CSF administration upon bone tumor growth. These data demonstrate an osteoclast-dependent G-CSF-induced stimulation of tumor growth in bone.;Bisphosphonates, drugs which disrupt osteoclast function, are routinely used to treat complications of bone metastasis. While in vitro studies suggest that bisphosphonates have anti-tumor effects, this has not been definitively shown in vivo. We evaluated the impact of bisphosphonate treatment on tumor cell growth in osteoclast-defective mice. Bisphosphonate-treated osteoclast-defective mice had decreased tumor growth in bone by 40% compared to vehicle-treated osteoclast-defective mice. This data strongly suggests an osteoclast-independent role for bisphosphonate therapy in bone metastasis.