Soluble receptor activator of nuclear factor-kB ligand : involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment

了解癌细胞如何诱导骨转移对于确定控制骨转移的新疗法至关重要。通过模拟与乳腺癌诱导的骨转移相关的骨溶解变化的小鼠模型，我们发现组织蛋白酶G是在肿瘤骨（TB）界面上调的蛋白酶。此外，我们发现组织蛋白酶G能够脱落核因子- kb配体受体激活因子（RANKL）的胞外结构域，产生能够诱导破骨细胞前体分化和激活的活性可溶性版本（sRANKL）。组织蛋白酶G的主要来源似乎是破骨细胞。此外，我们发现在体内抑制组织蛋白酶G可以减少乳腺肿瘤。诱导骨质溶解。接下来，我们研究了一种竞争性抑制剂sRANKL的预防作用，骨蛋白融合蛋白（OCIF）在乳房肿瘤细胞植入诱导骨溶解前（前）、诱导骨溶解后（后）或整个实验期间（整个）给予小鼠。在OCIF治疗前、治疗后和整个治疗组中，tb界面的肿瘤生长均受到显著抑制。治疗前、治疗后及全组骨破坏程度均显著降低。此外，无论治疗时间如何，OCIF治疗组的破骨细胞明显减少。总之，我们的数据表明，在结核界面抑制组织蛋白酶G活性可能是治疗靶点，而由组织蛋白酶G产生的sRANKL是预防和治疗乳腺癌骨转移的潜在靶点。

Understanding how cancer cells induce bone metastases is essential for the identification of new therapies to control bone metastasis. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G to be proteases that are up-regulated at the tumor bone(TB)-interface. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of receptor activator of nuclear factor-KB ligand(RANKL), generating active soluble version(sRANKL) that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G seems to be osteoclasts. Furthermore, we showed that in vivo inhibition of cathepsin G reduces mammary tumor. induced osteolysis.Next we examined the preventive effects of a competitive inhibitor of sRANKL, osteoprotegrin fusion protein(OCIF) was administered to mice before osteolysis induction by implantation of mammary tumor cells(pre), after osteolysis induction(post) or during the entire experimental period(whole). Tumor growth at the TB-interface was significantly suppressed in the pre as well as the post and whole treatment groups of OCIF. The extent of bone destruction was significantly reduced in the pre, post and whole treatment groups. In addition, significantly fewer osteoclasts wereobserved in the OCIF treatment groups regardless of treatment period.Together, our data indicate that inhibition of cathepsin G activity at the TB interface could be therapeutic targets, and sRANKL which is generated by cathepsin G is a potentially target for prevention as well as treatment of breast cancer bone metastasis.