Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone

Abstract

CXCR4 regulates hematopoietic and tumor cell homing to bone, but its role during osteoclast (OC) development is unknown. We investigated the role of CXCR4 in osteoclastogenesis and in a model of bone metastasis. Compared with controls, mice reconstituted with CXCR4 null hematopoietic cells exhibited elevated markers of bone resorption, increased OC perimeter along bone, and increased bone loss. CXCR4؊/؊ OCs demonstrated accelerated differentiation and enhanced bone resorption in vitro. Furthermore, tumor growth specifically in bone was significantly increased in mice reconstituted with CXCR4؊/؊ hematopoietic cells. Finally, enhancement of bone tumor growth in the absence of CXCR4 was abrogated with the OC inhibitor, zoledronic acid. These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity.bone metastasis ͉ osteoclast B one metastases are a significant cause of morbidity, causing pain, pathologic fractures, spinal cord compression, and hypercalcemia (1). Tumor cells that reach the bone marrow (BM) can stimulate one or both types of cells involved in bone remodeling, namely osteoblasts (stromal cell origin) or osteoclasts (OCs) (hematopoietic cell lineage), leading to new bone formation and osteoblastic lesions or bone loss and osteolytic lesions, respectively. OC resorption releases bone matrix-derived growth factors that can enhance local tumor growth (1-3). Disruption of OC resorption can decrease tumor growth in bone (3), and we have recently shown that pharmacologic enhancement of OC activity with granulocyte-colony stimulating factor increases tumor growth in bone in mice (4).CXCR4 is a seven-transmembrane G protein-coupled receptor expressed by many cell types, including hematopoietic, endothelial, stromal, and neuronal cells (5). Stromal cell-derived factor-1 (SDF-1) (or CXCL12) is the only known ligand for CXCR4 and is produced by multiple BM cell types, including stromal cells, osteoblasts, and OCs (6-8). CXCR4/SDF-1 are critical molecules in the process of hematopoietic stem cell (HSC) homing to and egress from the BM (9, 10). Gene-targeted disruptions of CXCR4 and SDF-1 are embryonic lethal, but examination of late-stage embryos reveal diminished HSC homing to the fetal BM (11-13). Additionally, inhibitors of either SDF-1 or CXCR4 have been shown to impair BM engraftment in transplant models (5). Small molecule inhibitors of CXCR4 mobilize HSCs and progenitor cells from the BM into the peripheral blood. Clinical trials are underway using CXCR4 inhibitors to mobilize and collect HSCs/hematopoietic progenitor cells from the peripheral blood in preparation for stem cell transplantation for malignant BM diseases (14).Signaling through CXCR4 has been shown to have both stimulatory and inhibitory roles on various hematopoietic cells, including promoting survival and proliferation of HSCs (5), inducing apoptosis in T cells (15), or causing quiescence in neural progenitors (16). The s...

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