Abstract
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 24h). 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.
| Original language | English (US) |
|---|---|
| Journal | Journal of Cellular Biochemistry |
| DOIs | |
| State | Accepted/In press - Jan 1 2017 |
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Keywords
- Animal model
- Microarray
- Post-traumatic joint contracture
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Intra-articular injection of a substance P inhibitor affects gene expression in a joint contracture model. / Morrey, Mark E.; Sanchez-Sotelo, Joaquin; Lewallen, Eric A.; An, Kai Nan; Grill, Diane E.; Steinmann, Scott P.; Yao, Jie J.; Salib, Christopher G.; Trousdale, William H.; Reina, Nicolas; Maradit Kremers, Hilal D; Lewallen, David G.; van Wijnen, Andre J; Abdel, Matthew.
In: Journal of Cellular Biochemistry, 01.01.2017.Research output: Contribution to journal › Article
}
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 - Maradit Kremers, Hilal D
AU - Lewallen, David G.
AU - van Wijnen, Andre J
AU - Abdel, Matthew
PY - 2017/1/1
Y1 - 2017/1/1
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 24h). 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 24h). 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
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
ER -