AdipoRon reduces TGFβ1‐mediated collagen deposition in vitro and alleviates knee stiffness in vivo

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin lev...

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Bibliographic Details
Published in:Journal of cellular physiology 2024-02, Vol.239 (2), p.e31168-n/a
Main Authors: Dudakovic, Amel, Limberg, Afton K., Bothun, Cole E., Dilger, Oliver B., Bayram, Banu, Bettencourt, Jacob W., Salmons, Harold I., Thaler, Roman, Karczewski, Daniel C., Owen, Aaron R., Iyer, Varun G., Payne, Ashley N., Carstens, Mason F., Wijnen, Andre J., Berry, Daniel J., Sanchez‐Sotelo, Joaquin, Morrey, Mark E., Abdel, Matthew P.
Format: Article
Language:English
Subjects:
Adiponectin
AdipoRon
Animal behavior
Animals
arthrofibrosis
Arthroplasty (knee)
Arthroplasty, Replacement, Knee
Biomechanics
Collagen
Collagen - metabolism
Deposition
Female
fibroblast
Fibroblasts
Humans
Immobilization
In vivo methods and tests
Joint Diseases - drug therapy
Joint Diseases - metabolism
Knee
Knee Joint - metabolism
Mesenchymal stem cells
Mice
Mice, Inbred C57BL
mRNA
myofibroblast
Piperidines - pharmacology
Stem cells
Stiffness
TGFβ1
total knee arthroplasty (TKA)
Transforming Growth Factor beta1 - pharmacology
Transforming growth factor-b1
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Summary:Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti‐fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFβ1‐mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFβ1‐induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA‐seq analysis corroborated the anti‐myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle‐treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.31168