Impaired Bone Matrix Alignment Induced by Breast Cancer Metastasis

Bone matrix exhibits highly anisotropic features derived from collagen/apatite orientation, that determine the mechanical function of bone tissue. Breast cancer is highly metastatic to bone tissue and causes osteolytic lesions through osteoclast activation. Nevertheless, the effects of osteoclast activation induced by cancer bone metastasis on bone microstructure, a notable aspect of the bone quality, remains uncertain. In the present study, the effects of osteolytic bone metastasis on the anisotropic microstructure of the bone matrix, particularly the integrity of collagen fibril orientation was investigated. Interestingly, hyperactivation of osteoclasts was induced by osteolytic breast cancer cells both in vivo and in vitro. The cancer cells-derived conditioned medium induced an increased number of nuclei and more specific podosome structures in osteoclasts. These results indicate the resorptive capacity of a single osteoclast was abnormally upregulated in the cancer-mediated environment, causing a geometrical aberration in 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 the metastatic bone exhibited a significantly disorganized architecture.