3 years ago

Intra-articular Injection of a Substance P Inhibitor Affects Gene Expression in a Joint Contracture Model

Nicolas Reina, Jie J. Yao, Matthew P. Abdel, Kai-Nan An, Mark E. Morrey, Andre J. van Wijnen, Eric A. Lewallen, Diane E. Grill, David G. Lewallen, Hilal M. Kremers, William H. Trousdale, Scott P. Steinmann, Christopher G. Salib, Joaquin Sanchez-Sotelo
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 hours). 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. This article is protected by copyright. All rights reserved

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jcb.26256

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