Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia ; Skeletal Biology and Forensic Anatomy Research Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
PLoS One. 2013 Sep 12;8(9):e68103. doi: 10.1371/journal.pone.0068103. eCollection 2013.
Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.
骨转移严重削弱了患者的身体机能，对转移性乳腺癌女性的生活质量产生了重大影响。治疗选择有限，为了开发更具针对性的治疗方法，有必要深入了解导致骨损伤发展的复杂机制。有趣的是，虽然前列腺来源的骨转移以混合或成骨病变为特征，而乳腺来源的骨转移则以溶骨性病变为特征，这表明存在独特的调节模式。本研究旨在测量 MDA-MB-231 人乳腺癌细胞经胫骨内注射入严重联合免疫缺陷 (SCID) 小鼠左侧胫骨后，在骨损伤发展的两个时间点（18 天和 36 天）时，骨形成和骨吸收活性的变化。对侧胫骨用作对照。提取胫骨并进行未脱钙组织形态计量学分析。我们提供的证据表明，暴露于 MDA-MB-231 细胞后观察到的早期骨丢失是由于矿化沉积率显著降低，而不是骨吸收水平增加所致。这表明在乳腺癌细胞存在的情况下，成骨细胞活性受损，这与之前报道的破骨细胞依赖性骨丢失相反。此外，DKK-1 和 Noggin 的 mRNA 表达在 MDA-MB-231 细胞系中得到证实，两者均拮抗成骨细胞调节途径。注射癌细胞后观察到的骨丢失是由于骨小梁的整体变薄，而不是骨组织基质的穿孔（分别通过小梁宽度和小梁分离来测量），这表明有机会逆转癌症引起的骨变化。这些对溶骨性骨损伤发展机制的新见解可能对开发转移性乳腺癌患者的新治疗策略具有重要意义。
