Disruption of collagen/apatite alignment impairs bone mechanical function in osteoblastic metastasis induced by prostate cancer

Abstract

Prostate cancer (PCa) frequently metastasizes to the bone, generally inducing osteoblastic alterations that increase bone brittleness. Although there is growing interest in the management of the physical capability of patients with bone metastasis, the mechanism underlying the impairment of bone mechanical function remains unclear. The alignment of both collagen fibrils and biological apatite (BAp) c-axis, together with bone mineral density, is one of the strongest contributors to bone mechanical function. In this study, we analyzed the bone microstructure of the mouse femurs with and without PCa cell inoculation. Histological assessment revealed that the bone-forming pattern in the PCa-bearing bone was non-directional, resulting in a spongious structure, whereas that in the control bone was unidirectional and layer-by-layer, resulting in a compact lamellar structure. The degree of preferential alignment of collagen fibrils and BAp, which was evaluated by quantitative polarized microscopy and microbeam X-ray diffraction, respectively, were significantly lower in the PCa-bearing bone than in the control bone. Material parameters including Young's modulus and toughness, measured by the three-point bending test, were simultaneously decreased in the PCa-bearing bone. Specifically, there was a significant positive correlation between the degree of BAp c-axis orientation and Young's modulus. In conclusion, the impairment of mechanical function in the PCa-bearing bone is attributable to disruption of the anisotropic microstructure of bone in multiple phases. This is the first report demonstrating that cancer bone metastasis induces disruption of the collagen/BAp alignment in long bones, thereby impairing their mechanical function.

A paradigm shift for bone quality in dentistry: A literature review

“…The degree of BAp c-axis orientation significantly and positively correlated with the mechanical parameter of bone not only in regenerated bone, but also in other bones such as intact and pathological bones [83,84]. Interestingly, this correlation was also seen in tooth dentin [85].…”

“…A negative relationship between the amount of AGE cross-links and the degree of BAp orientation is also suggested [85]. Moreover, synchronous alteration of anisotropic features in osteocyte network and BAp/collagen arrangement was reported [83,84,153,154]. Future studies are expected to provide insight into the potential applications of bone quality parameters for clinical use in prosthodontic dentistry as well as orthopedic fields.…”

“…The degree of bone regeneration [21,87] and the pathological conditions of diseased bone including some types of osteoporosis [88][89][90], osteoarthritis [91], osteopetrosis [92], and cancer metastasis [83,84] were reported to be assessed using the degree of BAp orientation. For example, in the primary type osteoporosis induced by estrogen deficiency, the degree of BAp c-axis orientation both in the cortical and trabecular bone of lumber vertebrae increases along the craniocaudal axis in which principal stress is applied [88].…”

Alteration of osteoblast arrangement via direct attack by cancer cells: New insights into bone metastasis

“…Tumor invasion and metastasis effect dynamic changes in targeted organs both histologically and genetically3. Interestingly, our recent study revealed that cancer cells alter the anisotropic microstructure of metastasized bone45. Homing of cancer cells to bone induces disrupted mechanical function derived from the disorganized microstructure associated with the less aligned crystallographic structure of apatite c -axis with the hexagonal lattice of the P6 3 /m space group.…”

“…Recently, we had established a bone-mimetic anisotropic culture model by controlling the orientation of the substrate collagen11. Further development of the culture model by combining the artificially-controlled anisotropic culture substrate with the cancer-bone coculture system is necessary to study the cellular mechanisms behind the metastasis-mediated disorganization of the anisotropic bone microstructure45. Here, focusing on the cellular orientation in response to the collagen molecular anisotropy, coculture of cancer cells and osteoblasts was performed on an artificially controlled oriented collagen scaffold.…”