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.
Tumor growth is increased in bone but not in lung or s.c. tissue of CXCR4-/- mice. (A)In vivo bioluminescence imaging after LV injection of B16-FL cells. Photon flux was quantitated in fixed region of interest (ROI) in the tibia/femur bones. *, P < 0.008 at all time points, two-tailed t test; n = 11 WT, n = 12 CXCR4-/-. (B)In vivo bioluminescence imaging after s.c. injection of B16-FL. Photon flux was quantitated in fixed ROI in the dorsal tumors. P = 0.1 day 5, P = 0.5 day 7, P = 0.6 day 10, P = 0.4 day 14, two-tailed t test; n = 5 WT, n = 5 CXCR4-/-. (C)In vivo bioluminescence imaging after i.v. injection of B16-FL. Photon flux was quantitated in fixed ROI in the lung area. P = 0.8 day 7, P = 0.7 day 9, P = 0.4 day 12, P = 0.1 day 16, two-tailed t test; n = 5 WT, n = 5 CXCR4-/-. (D) Representative images of WT (Left) vs. CXCR4-/- (Right) mice on the final day of imaging from each tumor experiment. (Top) Day 12 LV. (Middle) Day 14 s.c. (Bottom) Day 16 i.v.
References:
Hirbe A, Rubin J, Uluçkan O, Morgan E, Eagleton M, Prior J, Piwnica-Worms D, Weilbaecher K. Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone. Proc Natl Acad Sci USA 2007; 104(35): 14062-7.
