Figure 4.
Figure 4. Osteolytic effects of MIP-1α in mice bearing intramedullary CHO/MIP-1α-secreting tumors induced by direct intracardiac inoculation of tumor cells. (A) Radiographs of lower limbs of nude mice 3 weeks after intracardiac inoculation of either CHO cell clones showing radiolucent lytic lesions (arrows) in a CHO/MIP-1α-bearing mouse but not CHO/EV mouse. (B) The number of lytic lesions in hind limbs of CHO/MIP-1α tumor-bearing mice was significantly greater than in control CHO/EV tumor-bearing mice. There were no lesions visible in mice injected with PBS. (C) Development of osteolytic lesions in CHO/MIP-1α tumor-bearing mice was associated with hypercalcemia. Whole blood ionized calcium levels in CHO/EV cells were not significantly different from those in mice injected with PBS. Upper limit of reference range for ionized calcium in nude mice: 1.3 mM (dashed line). See “Statistical analysis.” (D) Representative photomicrographs of tibiae of mice with intramedullary tumors induced by intracardiac inoculation of CHO/MIP-1α cells (top panels) and CHO/EV cells (bottom panels). Serial sections were stained with H&E (right panels) or stained for TRAP activity (left panels). A global increase in the number of TRAP+ osteoclasts is evident in the section of CHO/MIP-1α tumor-bearing mouse tibia, compared with that of tibia from mouse bearing CHO/EV tumor. An increased number of osteoclasts staining intensely positive for TRAP can be seen not only at CHO/MIP-1α tumor-bone interface but also along CHO/MIP-1α tumor-growth plate interface (short arrows). In the CHO/MIP-1α section, the marked increase in osteoclast activity is evident even on the primary spongiosum side of the growth plate where no tumor is present. In contrast, in the CHO/EV tumor, no osteoclasts are present even where the tumor is closely apposed to the growth plate (long arrows). T indicates tumor; gp, growth plate; m, normal marrow. Original magnification, × 20. (E) Representative photomicrograph of CHO/MIP-1α tumor in mouse tibia following induction of intramedullary metastases via intracardiac inoculation of CHO/MIP-1α cells, stained with H&E (right panels) or for TRAP activity (left panels). Top panels (at low original magnification, × 20) show a marked increase in number of TRAP+ osteoclasts evident all along the tumor-bone interface. In the bottom panels (depicting the inset) (at high original magnification, × 40), an intensely stained multinucleated osteoclast (OCL) is evident at the leading edge of the CHO/MIP-1α tumor.

Osteolytic effects of MIP-1α in mice bearing intramedullary CHO/MIP-1α-secreting tumors induced by direct intracardiac inoculation of tumor cells. (A) Radiographs of lower limbs of nude mice 3 weeks after intracardiac inoculation of either CHO cell clones showing radiolucent lytic lesions (arrows) in a CHO/MIP-1α-bearing mouse but not CHO/EV mouse. (B) The number of lytic lesions in hind limbs of CHO/MIP-1α tumor-bearing mice was significantly greater than in control CHO/EV tumor-bearing mice. There were no lesions visible in mice injected with PBS. (C) Development of osteolytic lesions in CHO/MIP-1α tumor-bearing mice was associated with hypercalcemia. Whole blood ionized calcium levels in CHO/EV cells were not significantly different from those in mice injected with PBS. Upper limit of reference range for ionized calcium in nude mice: 1.3 mM (dashed line). See “Statistical analysis.” (D) Representative photomicrographs of tibiae of mice with intramedullary tumors induced by intracardiac inoculation of CHO/MIP-1α cells (top panels) and CHO/EV cells (bottom panels). Serial sections were stained with H&E (right panels) or stained for TRAP activity (left panels). A global increase in the number of TRAP+ osteoclasts is evident in the section of CHO/MIP-1α tumor-bearing mouse tibia, compared with that of tibia from mouse bearing CHO/EV tumor. An increased number of osteoclasts staining intensely positive for TRAP can be seen not only at CHO/MIP-1α tumor-bone interface but also along CHO/MIP-1α tumor-growth plate interface (short arrows). In the CHO/MIP-1α section, the marked increase in osteoclast activity is evident even on the primary spongiosum side of the growth plate where no tumor is present. In contrast, in the CHO/EV tumor, no osteoclasts are present even where the tumor is closely apposed to the growth plate (long arrows). T indicates tumor; gp, growth plate; m, normal marrow. Original magnification, × 20. (E) Representative photomicrograph of CHO/MIP-1α tumor in mouse tibia following induction of intramedullary metastases via intracardiac inoculation of CHO/MIP-1α cells, stained with H&E (right panels) or for TRAP activity (left panels). Top panels (at low original magnification, × 20) show a marked increase in number of TRAP+ osteoclasts evident all along the tumor-bone interface. In the bottom panels (depicting the inset) (at high original magnification, × 40), an intensely stained multinucleated osteoclast (OCL) is evident at the leading edge of the CHO/MIP-1α tumor.

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