Targeting RANKL for the treatment of muscle and bone defects in cachexia

靶向 RANKL 治疗恶病质肌肉和骨骼缺陷

• 批准号: 10751604
• 负责人: Andrea Bonetto
• 金额: $ 45.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751604
• 关键词: Targeting; RANKL; treatment; muscle; bone

PROJECT SUMMARY Cachexia is defined by abnormal loss of body weight and muscle mass that occurs secondary to chronic diseases, such as cancer. It is estimated that musculoskeletal complications affect up to 80% of patients diagnosed with cancer, dramatically impacting patient survival. Thus, there is an urgent need to develop novel treatments for cachexia-related musculoskeletal symptoms. Our recently published observations showing that cancer cachexia can present with bone loss, even in the absence of direct metastases to bone, suggest that tumor-derived soluble factors may play a critical role in the onset of such skeletal phenotype. In this regard, our preliminary findings suggest that receptor activator of NFkB ligand (RANKL), a factor involved in osteoclast- induced bone resorption, plays a causative role in cancer-associated musculoskeletal complications. In our published and preliminary studies we found that patients affected with ovarian cancer present cachexia, as well as elevated RANKL and CTX-I, a marker of bone resorption. Similarly, mice bearing ES-2 ovarian tumors present with muscle and bone loss, along with high RANKL and bone resorption, also consistent with high positivity for the osteoclast marker, TRAP, as well as dramatic osteocyte death. Contrarily, mice carrying C26 tumors, characterized by low RANKL expression, substantially maintain their bone mass, despite evidence of muscle wasting. Interestingly, myotubes exposed to recombinant RANKL undergo atrophy, similar to mice infected with AAV-RANKL or bearing C26 cells overexpressing RANKL, whereas the use of anti-RANKL neutralizing antibodies preserves myotube size in C2C12 myotubes co-cultured with ES-2 cells and counteracts bone and muscle loss in ES-2 tumor hosts. The objective of this proposal is to define the mechanisms by which RANKL-expressing tumors participate in bone and muscle loss in cachexia. Our central hypothesis is that tumor-derived RANKL participates in the activation of bone resorption, and triggers mechanisms adversely affecting muscle mass. In Aim 1, we will determine the effects of tumor-derived RANKL on bone loss in the absence of bone metastases. We hypothesize that tumor-derived RANKL directly activates bone resorption. In Aim 2, we will elucidate the mechanism(s) responsible for RANKL-induced muscle wasting. We hypothesize that activation of the RANKL/RANK-dependent pathway in skeletal muscle is sufficient to induce atrophy and exacerbate cachexia. In Aim 3, we will validate antiresorptive therapies to preserve muscle size and function in mice bearing RANKL-expressing tumors. We hypothesize that tumor-derived RANKL, along with IL-6 consequential to bone resorption, negatively impact muscle. The findings from the proposed studies will define the mechanistic effects of RANKL in cachexia and identify RANKL as a new therapeutic target for the treatment of musculoskeletal complication associated with non- metastatic RANKL-expressing cancers. These results will also open new avenues for cachexia research.

项目摘要 恶病质的定义是体重和肌肉质量的异常损失，发生继发于慢性 疾病，如癌症。据估计，肌肉骨骼并发症影响高达80%的患者 被诊断出患有癌症，极大地影响了患者的生存。因此，小说的发展就显得尤为迫切 恶病质相关的肌肉骨骼症状的治疗。我们最近发表的观察表明， 癌症恶病质可以表现为骨丢失，即使没有直接转移到骨，这表明， 肿瘤衍生的可溶性因子可能在这种骨骼表型的发生中起关键作用。在这方面， 初步研究结果表明，NF κ B配体受体激活因子（RANKL），一种参与破骨细胞增殖的因子， 诱导骨吸收，在癌症相关的肌肉骨骼并发症中起着致病作用。 在我们发表的和初步的研究中，我们发现卵巢癌患者会出现恶病质， 以及RANKL和CTX-I（骨吸收的标志物）升高。同样，携带ES-2卵巢肿瘤的小鼠 存在肌肉和骨丢失，沿着高RANKL和骨吸收，也与高 破骨细胞标志物TRAP的阳性以及骨细胞的急剧死亡。首先，携带C26的小鼠 肿瘤，其特征在于低RANKL表达，基本上保持其骨量，尽管有证据表明， 肌肉萎缩有趣的是，暴露于重组RANKL的肌管发生萎缩，与小鼠相似。 感染AAV-RANKL或携带过表达RANKL的C26细胞，而使用抗RANKL 中和抗体保留了与ES-2细胞共培养的C2 C12肌管中的肌管大小， ES-2肿瘤宿主的骨和肌肉损失。 本提案的目的是确定表达RANKL的肿瘤参与 恶病质中的骨骼和肌肉损失。我们的中心假设是肿瘤源性RANKL参与了 激活骨吸收，并触发对肌肉质量产生不利影响的机制。在目标1中，我们 确定在无骨转移的情况下肿瘤源性RANKL对骨丢失的影响。我们假设 肿瘤来源的RANKL直接激活骨吸收。在目标2中，我们将阐明机制 导致RANKL诱导的肌肉萎缩。我们假设RANKL/RANK依赖性的激活 在骨骼肌中的代谢途径足以诱导萎缩并加重恶病质。在目标3中，我们将验证 抗再吸收疗法，以保护携带RANKL表达肿瘤的小鼠的肌肉大小和功能。我们 假设肿瘤来源RANKL，沿着IL-6导致骨吸收， 肌肉. 拟定研究的结果将定义RANKL在恶病质中的机制作用，并确定 RANKL作为一种新的治疗靶点，用于治疗非骨关节炎相关的肌肉骨骼并发症 转移性RANKL表达癌症。这些结果也将为恶病质研究开辟新的途径。