Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

Abstract

Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

Oral squamous cell carcinoma cells induce osteoclast differentiation by suppression of osteoprotegerin expression in osteoblasts

“…23,24,27 We demonstrate in our study that fixed BHY cells induced mainly TRAP þ mononuclear and binuclear cells but not MNCs. These results strongly suggest that living cell-to-cell contact among BHY cells and POBs is essential for osteoclast formation.…”

“…29 On the other hand, not all cancers express RANKL and cell-to-cell contact between cancer cells and host cells does not always lead to RANKL expression. [26][27][28] Ohshiba et al 27 recently showed that MDA-231 cells, a breast cancer cell line, do not express RANKL. Nevertheless, addition of MDA-231 cells to cocultures of mouse BMCs and POBs induced osteoclast formation without osteotropic factors present.…”

“…30 However, cell-to-cell contact between tumor cells and osteoblasts/ stromal cells is thought to be essential for the production of cytokines and matrix metalloproteinase. 9,27 To investigate this idea, cocultures of mouse BMCs and POBs were separated from BHY cells using transwells and further cultured for 6 days in the absence of osteotropic factors. Osteoclast formation induced by BHY cells was strongly suppressed, but numerous TRAP þ mononuclear and binuclear cells were observed in separate cultures (Fig.…”

“…25 Interesting and controversial new questions have arisen concerning the direct expression and production of RANKL by human cancer cells: Some evidence suggests that RANKL/OPG expression ratio in osteoblasts/stromal cells is the critical factor regulating osteoclastogenesis under both physiological and pathological conditions. 9,26,27 Moreover, T lymphocytes appear to play a role in the regulation of bone resorption through RANKL expression. 28 On the other hand, cancer cells expressing RANKL directly were able to induce osteoclastogenesis even in the absence of other accessory cells.…”

Interface membrane fibroblasts around aseptically loosened endoprostheses express MMP‐13

“…MMPs have been detected in osteolytic bone lesions caused by tumors forming bone metastases, 33 and in vivo there is a marked expression of MMP-13 in bone metastases of mammary tumors. 34 In a mouse model, tumor-induced osteolysis was decreased by TIMPs. 35 This also suggests that osteolysis is closely connected with MMP activity, and that MMPs might be a therapeutic target to prevent osteolytic bone destruction.…”