Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis

M. E. Tibbo; A. K. Limberg; C. G. Salib; T. W. Turner; A. R. McLaury; A. G. Jay; J. W. Bettencourt; J. M. Carter; D. J. Berry; M. E. Morrey; J. Sanchez-Sotelo; M. P. Abdel; B. Bolon; A. J. van Wijnen

doi:10.1302/2046-3758.96.BJR-2019-0272.R2

Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis

M. E. Tibbo, A. K. Limberg, C. G. Salib, T. W. Turner, A. R. McLaury, A. G. Jay, J. W. Bettencourt, J. M. Carter, D. J. Berry, M. E. Morrey, J. Sanchez-Sotelo, M. P. Abdel, B. Bolon, A. J. van Wijnen

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Abstract

Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis.

Original language	English (US)
Pages (from-to)	302-310
Number of pages	9
Journal	Bone and Joint Research
Volume	9
Issue number	6
DOIs	https://doi.org/10.1302/2046-3758.96.BJR-2019-0272.R2
State	Published - Jun 2020

Keywords

Acquired idiopathic stiffness
Arthrofibrosis
Joint fibrosis
Ketotifen
Myofibroblast
Total knee arthroplasty

ASJC Scopus subject areas

Surgery
Orthopedics and Sports Medicine

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10.1302/2046-3758.96.BJR-2019-0272.R2

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Tibbo, M. E., Limberg, A. K., Salib, C. G., Turner, T. W., McLaury, A. R., Jay, A. G., Bettencourt, J. W., Carter, J. M., Berry, D. J., Morrey, M. E., Sanchez-Sotelo, J., Abdel, M. P., Bolon, B., & van Wijnen, A. J. (2020). Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis. Bone and Joint Research, 9(6), 302-310. https://doi.org/10.1302/2046-3758.96.BJR-2019-0272.R2

Tibbo, ME, Limberg, AK, Salib, CG, Turner, TW, McLaury, AR, Jay, AG, Bettencourt, JW, Carter, JM, Berry, DJ, Morrey, ME, Sanchez-Sotelo, J, Abdel, MP, Bolon, B & van Wijnen, AJ 2020, 'Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis', Bone and Joint Research, vol. 9, no. 6, pp. 302-310. https://doi.org/10.1302/2046-3758.96.BJR-2019-0272.R2

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title = "Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis",

abstract = "Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis.",

keywords = "Acquired idiopathic stiffness, Arthrofibrosis, Joint fibrosis, Ketotifen, Myofibroblast, Total knee arthroplasty",

author = "Tibbo, {M. E.} and Limberg, {A. K.} and Salib, {C. G.} and Turner, {T. W.} and McLaury, {A. R.} and Jay, {A. G.} and Bettencourt, {J. W.} and Carter, {J. M.} and Berry, {D. J.} and Morrey, {M. E.} and J. Sanchez-Sotelo and Abdel, {M. P.} and B. Bolon and {van Wijnen}, {A. J.}",

note = "Publisher Copyright: {\textcopyright} 2020 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/.",

year = "2020",

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doi = "10.1302/2046-3758.96.BJR-2019-0272.R2",

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pages = "302--310",

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issn = "2046-3758",

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T1 - Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis

AU - Tibbo, M. E.

AU - Limberg, A. K.

AU - Salib, C. G.

AU - Turner, T. W.

AU - McLaury, A. R.

AU - Jay, A. G.

AU - Bettencourt, J. W.

AU - Carter, J. M.

AU - Berry, D. J.

AU - Morrey, M. E.

AU - Sanchez-Sotelo, J.

AU - Abdel, M. P.

AU - Bolon, B.

AU - van Wijnen, A. J.

N1 - Publisher Copyright: © 2020 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/.

PY - 2020/6

Y1 - 2020/6

N2 - Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis.

AB - Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis.

KW - Acquired idiopathic stiffness

KW - Arthrofibrosis

KW - Joint fibrosis

KW - Ketotifen

KW - Myofibroblast

KW - Total knee arthroplasty

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Anti-fibrotic effects of the antihistamine ketotifen in a rabbit model of arthrofibrosis

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