Human tumour-associated macrophages differentiate into osteoclastic bone-resorbing cells

Macrophages are commonly found within osteolytic secondary carcinomas in bone, but the manner in which these cells contribute to malignant bone resorption is uncertain. Macrophages isolated from primary breast carcinomas were co-cultured for up to 21 days with UMR 106 rat osteoblast-like cells on bone slices and glass coverslips in the presence and absence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF). Cell cultures were then assessed for the presence of phenotypic markers of macrophage and osteoclast differentiation. Isolated cells were negative for osteoclast markers including tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and the ability to carry our lacunar bone resorption, but were positive for CD11b and CD14, macrophage markers which are not present on osteoclasts. In 21-day co-cultures of breast carcinoma tumour-associated macrophages (TAMs) and UMR 106 cells, incubated in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP- and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed. Contact with UMR 106 cells and the presence of 1,25(OH)2D3 and M-CSF were absolute requirements for differentiation of human breast carcinoma TAMs into mature functional osteoclasts. TAM-osteoclast differentiation may represent an important cellular mechanism of osteolysis in metastatic skeletal carcinomas.