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

Abstract

Destruction of bone is often a consequence of the development of a primary benign or malignant tumour or tumourlike lesion in bone. This results in considerable morbidity, including bone pain and pathological fracture. Although the osteolysis associated with the enlargement of primary mesenchymal tumours and tumour-like lesions of bone is thought to be carried out by osteoclasts, the precise cellular and humoral mechanisms which contribute are unknown. 1,2Osteoclasts are specialised, multinucleated, bone-resorbing cells which form part of the mononuclear phagocyte system.3 They are formed by the fusion of circulating mononuclear precursor cells of haematopoietic origin. Studies in vitro have defined the ontogeny of the osteoclast and characterised the essential cellular and humoral factors which are required for its differentiation from haematopoietic and circulating osteoclast precursors. In both the mouse and man, mononuclear osteoclast precursors circulate in the monocyte fraction and express a monocyte/macrophage rather than a mature osteoclast phenotype. 4-6 These circulating precursors express the receptor activator for nuclear factor B (RANK) and their differentiation into osteoclasts requires the presence of macrophage-colony stimulating factor (M-CSF) and involves a receptor-ligand interaction with osteoblasts/bone stromal cells which express the membrane-bound ligand for RANK (RANKL). 7,8 In previous studies, we have shown that tumour-associated macrophages (TAMs) isolated from primary human breast and mouse mammary carcinomas, when co-cultured with bone-derived stromal cells in the presence of 1,25 dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and M-CSF, are able to differentiate into multinucleated osteoclasts which can carry out extensive resorption of lacunar bone. 9,10 This finding is of interest with regard to the pathogenesis of tumour osteolysis since, in addition to an increase in osteoclast numbers, a prominent macrophage infiltrate is commonly found in primary and metastatic tumours of bone. [11][12][13] Osteoclasts are also required for the growth of metastatic and primary mesenchymal tumours of bone and osteolysis involves recruitment of osteoclast precursors and the activation of mature osteoclasts.

Transgenic expression of CSF-1 in CSF-1 receptor-expressing cells leads to macrophage activation, osteoporosis, and early death

“…In cancer, circuIating CSF-1 is elevated in myeloid and lymphoid leukemias [16] and in cancers of the female reproductive system [17]. In breast cancer, an increased accumulation of tumor-associated macrophages is correlated with poor prognosis [18 -20], and production of CSF-1 by tumor cells contributes to osteoclastogenesis from tumor-associated macrophages, leading to tumor-associated osteolysis [21].…”