TY - JOUR
T1 - Intra-articular injection of a substance P inhibitor affects gene expression in a joint contracture model
AU - Morrey, Mark E.
AU - Sanchez-Sotelo, Joaquin
AU - Lewallen, Eric A.
AU - An, Kai Nan
AU - Grill, Diane E.
AU - Steinmann, Scott P.
AU - Yao, Jie J.
AU - Salib, Christopher G.
AU - Trousdale, William H.
AU - Reina, Nicolas
AU - Kremers, Hilal M.
AU - Lewallen, David G.
AU - van Wijnen, Andre J.
AU - Abdel, Matthew P.
N1 - Funding Information:
We thank the members of the Abdel and van Wijnen Laboratories, including William Trousdale, Christopher Salib, Roman Thaler, and Amel Dudakovic for stimulating discussions. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers R01 AR049069 (to AJVW) and F32 AR068154 (to EAL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also appreciate the generous philanthropic support from the William H. and Karen J. Eby Foundation, as well as the Anna-Maria and Stephen Kellen Foundation. David Lewallen reports personal fees and other from Acuitive, Stryker, Pipeline Biomedical, Zimmer, and Ketai Medical Devices, as well as patents on selected hip and knee implants with royalties paid by Zimmer. He is also employed part time as the Medical Director for The American Joint Replacement Registry. Matthew Abdel has stock options with Imagen Technologies.
Funding Information:
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Grant numbers: F32 AR068154, R01 AR049069
Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - animal model
KW - microarray
KW - post-traumatic joint contracture
UR - http://www.scopus.com/inward/record.url?scp=85034631807&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034631807&partnerID=8YFLogxK
U2 - 10.1002/jcb.26256
DO - 10.1002/jcb.26256
M3 - Article
C2 - 28671282
AN - SCOPUS:85034631807
VL - 119
SP - 1326
EP - 1336
JO - Journal of supramolecular structure and cellular biochemistry
JF - Journal of supramolecular structure and cellular biochemistry
SN - 0730-2312
IS - 2
ER -