Intra-articular injection of a substance P inhibitor affects gene expression in a joint contracture model

Mark E. Morrey, Joaquin Sanchez-Sotelo, Eric A. Lewallen, Kai Nan An, Diane E. Grill, Scott P. Steinmann, Jie J. Yao, Christopher G. Salib, William H. Trousdale, Nicolas Reina, Hilal M. Kremers, David G. Lewallen, Andre J. van Wijnen, Matthew P. Abdel

研究成果: Article同行評審

8 引文 斯高帕斯(Scopus)

摘要

Substance P (SP), a neurotransmitter released after injury, has been linked to deregulated tissue repair and fibrosis in musculoskeletal tissues and other organs. Although SP inhibition is an effective treatment for nausea, it has not been previously considered as an anti-fibrotic therapy. Although there are extensive medical records of individuals who have used SP antagonists, our analysis of human registry data revealed that patients receiving these antagonists and arthroplasty are exceedingly rare, thus precluding a clinical evaluation of their potential effects in the context of arthrofibrosis. Therefore, we pursued in vivo studies to assess the effect of SP inhibition early after injury on pro-fibrotic gene expression and contractures in an animal model of post-traumatic joint stiffening. Skeletally mature rabbits (n = 24) underwent surgically induced severe joint contracture, while injected with either fosaprepitant (a selective SP antagonist) or saline (control) early after surgery (3, 6, 12, and 24 h). Biomechanical testing revealed that differences in mean contracture angles between the groups were not statistically significant (P = 0.27), suggesting that the drug neither mitigates nor exacerbates joint contracture. However, microarray gene expression analysis revealed that mRNA levels for proteins related to cell signaling, pro-angiogenic, pro-inflammatory, and collagen matrix production were significantly different between control and fosaprepitant treated rabbits (P < 0.05). Hence, our study demonstrates that inhibition of SP alters expression of pro-fibrotic genes in vivo. This finding will motivate future studies to optimize interventions that target SP to reduce the formation of post-traumatic joint contractures.

原文English
頁(從 - 到)1326-1336
頁數11
期刊Journal of Cellular Biochemistry
119
發行號2
DOIs
出版狀態Published - 2018 二月

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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