Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, United Kingdom.
Endocrinology. 2011 Feb;152(2):503-14. doi: 10.1210/en.2010-1087. Epub 2011 Jan 5.
Antiinflammatory glucocorticoid (GC) injections are extensively used to treat painful tendons. However, GC cause severe tissue wasting in other collagen-producing tissues such as skin and bone. The objective of this study was to determine the effects of GC on tenocytes and to explore strategies to protect against unwanted side effects of GC treatment. Cell survival, collagen production, and the induction of signaling pathways in primary human tenocytes treated with dexamethasone (Dex) were assessed. Antioxidant and growth factor approaches to protection were tested. Dex treatment resulted in reduced viable cell number, cell proliferation, and collagen production. Dex induced reactive oxygen species generation in tenocytes and strongly up-regulated the stress-response transcription factors FOXO1 and FOXO3A. Phosphorylation of ERK and protein kinase B/Akt, which regulate cell proliferation and also inhibit forkhead activity, was decreased. Chemical inhibition of ERK or Akt activity significantly reduced tenocyte cell number. Ameliorating the Dex-induced reduction in ERK or Akt activity by cotreatment with vitamin C or insulin protected against the Dex-induced reduction in cell number. Silencing FOXO1 prevented the Dex-induced reduction in collagen 1α1 expression. Cotreatment with vitamin C or insulin protected against the Dex-induced increase in FOXO and the Dex-induced inhibition of collagen 1α1 expression. Reduced ERK and Akt activation and increased forkhead signaling contribute to the negative effects of GC on tenocytes. Cotreatment therapies that target these signaling pathways are protective. Vitamin C in particular may be a clinically useable co-therapy to reduce connective tissue side effects associated with GC therapy.
抗炎糖皮质激素（GC）注射广泛用于治疗疼痛的肌腱。然而，GC 会导致皮肤和骨骼等其他产生胶原蛋白的组织严重消耗。本研究的目的是确定 GC 对肌腱细胞的影响，并探讨保护肌腱细胞免受 GC 治疗不良副作用的策略。评估了地塞米松（Dex）处理的原代人肌腱细胞的细胞存活、胶原蛋白产生和信号通路的诱导。测试了抗氧化和生长因子保护方法。Dex 处理导致活细胞数量、细胞增殖和胶原蛋白产生减少。Dex 在肌腱细胞中诱导活性氧的产生，并强烈上调应激反应转录因子 FOXO1 和 FOXO3A。调节细胞增殖并抑制叉头活性的 ERK 和蛋白激酶 B/Akt 的磷酸化减少。ERK 或 Akt 活性的化学抑制显著减少肌腱细胞数量。用维生素 C 或胰岛素共同处理减轻 Dex 诱导的 ERK 或 Akt 活性降低可防止 Dex 诱导的细胞数量减少。沉默 FOXO1 可防止 Dex 诱导的胶原蛋白 1α1 表达减少。用维生素 C 或胰岛素共同处理可防止 Dex 诱导的 FOXO 增加和 Dex 诱导的胶原蛋白 1α1 表达抑制。ERK 和 Akt 激活减少和叉头信号增加导致 GC 对肌腱细胞的负面影响。针对这些信号通路的联合治疗具有保护作用。维生素 C 特别可能是一种临床上可用的联合治疗方法，可减少与 GC 治疗相关的结缔组织副作用。
