Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA.
Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA.
Cytokine. 2022 Nov;159:155972. doi: 10.1016/j.cyto.2022.155972. Epub 2022 Aug 30.
Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.
肌肉骨骼疾病，如肌肉营养不良、恶病质、骨关节炎和类风湿性关节炎，会损害整体身体健康并降低存活率。患者会因骨骼、肌肉和关节的炎症和纤维化而出现局部和全身性的疼痛、功能障碍和运动障碍。白细胞介素-6（IL-6）家族细胞因子，尤其是 IL-6，与肌肉骨骼疾病和恶病质有关。在这里，我们发现，在小鼠胰腺癌恶病质中，循环中的 OSM 水平升高，并通过腺相关病毒（AAV）介导的野生型和 IL-6 缺陷型小鼠中鼠 OSM 的过表达，评估了白细胞介素-6 家族成员，即肿瘤坏死因子-α（OSM）对肌肉和骨骼的影响。使用高滴度 AAV-OSM 注射的初步研究产生了高循环 OSM 和 IL-6、血小板增多症、炎症和 4 天内 60%的死亡率，而没有肌肉损失。随后，为了模拟恶病质中的 OSM 水平，在野生型和 Il6 缺失型小鼠中使用低滴度的 AAV-OSM，观察到 4 周和 12 周的效果。AAV-OSM 导致注射侧的腓肠肌、胫骨前肌和股四头肌发生肌肉萎缩和纤维化，但在未注射侧未观察到这些影响。相比之下，OSM 导致局部和远处的小梁骨丢失，表现为骨体积、小梁数量和厚度减少，以及小梁分离增加。OSM 导致心脏功能障碍，包括射血分数降低和缩短分数降低。心肌的 RNA 测序显示，与炎症和纤维化相关的基因上调。在 IL-6 基因敲除型小鼠中，这些影响没有差异。因此，OSM 独立于 IL-6 诱导局部肌肉萎缩、全身骨丢失、组织纤维化和心脏功能障碍，表明 OSM 在具有这些特征的肌肉骨骼疾病中发挥作用，包括癌症恶病质。
