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

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          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.


          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).


          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).


          Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis.

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          Most cited references 35

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          The use of total protein stains as loading controls: an alternative to high-abundance single-protein controls in semi-quantitative immunoblotting.

          Western blots are used to estimate the relative concentrations of proteins of interest based on staining by specific antibodies. Quantitative measurements are often subject to error due to overloading of the loading control and over-reliance on normalization. We have found that at the protein concentrations normally used to quantify most low-abundance proteins of interest, frequently used single-protein loading controls, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and beta-actin, do not accurately reflect differences in protein concentration. Two total protein stains, SYPRO Ruby and Amido Black, were compared and found to be acceptable alternatives to single-protein controls. Although we cannot prove that high-abundance loading controls are inaccurate under all possible conditions, we conclude that the burden of proof should lie with the researcher to demonstrate that their loading control is reflective of quantitative differences in protein concentration.
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            Stiffness after total knee arthroplasty.

            Postoperative stiffness is a debilitating complication of total knee arthroplasty. Preoperative risk factors include limited range of motion, underlying diagnosis, and history of prior surgery. Intraoperative factors include improper flexion-extension gap balancing, oversizing or malpositioning of components, inadequate femoral or tibial resection, excessive joint line elevation, creation of an anterior tibial slope, and inadequate resection of posterior osteophytes. Postoperative factors include poor patient motivation, arthrofibrosis, infection, complex regional pain syndrome, and heterotopic ossification. The first steps in treating stiffness are mobilizing the patient and instituting physical therapy. If these interventions fail, options include manipulation, lysis of adhesions, and revision arthroplasty. Closed manipulation is most successful within the first 3 months after total knee arthroplasty. Arthroscopic or modified open lysis of adhesions can be considered after 3 months. Revision arthroplasty is preferred for stiffness from malpositioned or oversized components. Patients who initially achieve adequate range of motion (>90 degrees of flexion) but subsequently develop stiffness more than 3 months after surgery should be assessed for intrinsic as well as extrinsic causes.
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              Tryptase/Protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts.

              The mast cell product, tryptase, has recently been implicated to mediate fibrosis in the hypertensive heart. Tryptase has been shown to mediate noncardiac fibroblast function via activation of protease-activated receptor 2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase 1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal-regulated kinase 1/2 via protease-activated receptor 2. Blockade of protease activated receptor 2 with FSLLRY (10 μmol/L) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 μmol/L) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. In contrast, p38 mitogen-activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation. Treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals, indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α-smooth muscle actin and extra type III domain A (ED-A) fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease-activated receptor 2 and subsequent induction of extracellular signal-regulated kinase signaling.

                Author and article information

                Role: Orthopedic Surgery Resident
                Role: Research Assistant
                Role: Research Fellow
                Role: Undergraduate Research Student
                Role: Undergraduate Research Student
                Role: Post-doctoral Research Fellow
                Role: Graduate Research Student
                Role: Assistant Professor of Laboratory Medicine and Pathology
                Role: Veterinary Pathologist
                Role: Professor of Orthopedic Surgery and Consultant
                Role: Associate Professor of Orthopedic Surgery and Consultant
                Role: Professor of Orthopedic Surgery and Consultant
                Role: Professor of Biochemistry and Molecular Biology and Orthopedic Surgery
                Role: Professor of Orthopedic Surgery and Consultant
                Bone Joint Res
                Bone Joint Res
                Bone & Joint Research
                The British Editorial Society of Bone and Joint Surgery (London )
                23 July 2020
                June 2020
                : 9
                : 6
                : 302-310
                [1 ]org-divisionDepartment of Orthopedic Surgery, Mayo Clinic , Rochester, Minnesota, USA
                [2 ]org-divisionGEMpath, Inc. , Longmont, Colorado, USA
                [3 ]org-divisionDepartment of Orthopedic Surgery and Department of Biochemistry & Molecular Biology, Mayo Clinic , Rochester, Minnesota, USA
                Author notes
                Address correspondence to: Matthew P Abdel. E-mail: abdel.matthew@
                © 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.

                bjr, BJR
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                Mayo Clinic, Rochester, Minnesota, USA


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