Disruption of collagen matrix alignment in osteolytic bone metastasis induced by breast cancer

Abstract

Breast cancer is highly metastatic to bone tissue and causes osteolytic lesions through osteoclast activation. Although the effects of osteolytic metastasis on bone quantity have been well studied, whether osteoclast activation induced by cancer bone metastasis affects the bone microstructure, a notable aspect of the bone quality, remains uncertain. The aim of this study was to clarify the effect of osteolytic bone metastasis in breast cancer on the microstructure of the bone matrix, particularly the integrity of collagen fibril orientation. Osteolytic breast cancer cells induced hyperactivation of osteoclasts both in vivo and in vitro. Osteoclasts differentiated by culture of monocytes in the cancer cell-derived conditioned medium had an increased number of nuclei; more specific podosome structures were organized compared to osteoclasts differentiated in the control medium. These observations suggest that the resorptive capacity of a single osteoclast was abnormally upregulated in the cancer-involving environment, causing geometrically irregular resorption cavities. Histological studies on mouse femurs with metastasis of breast cancer MDA-MB-231 cells revealed that the osteoclasts in the metastatic bone were abnormally large and they generated resorption cavities that are irregular both in size and in shape. Notably, collagen matrix in newly formed bone in metastatic bone exhibited a significantly disorganized architecture. To the best of our knowledge, this is the first report demonstrating that osteolytic bone metastasis induces the disruption of bone matrix alignment, which determines the mechanical function of bone in both intact and diseased bone tissue.