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

Abstract

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.

Efficacy of ADIPOR1 and ADIPOR2 peptide‐agonist AdipoRon in preventing contracture in a rabbit model of arthrofibrosis

“…Our group recently investigated AdipoRon implementation in a mouse model of knee stiffness, and determined molecular and phenotypic evidence that AdipoRon mitigated contracture following serial dosing at 5 mg/kg for 6 weeks after contracture initiating surgery. 19 The early benefits of AdipoRon observed in the present investigation recapitulated these findings.…”

“…[16][17][18] Importantly, recent studies have determined that AdipoRon impaired TGFβ1-induced fibrosis phenotype in mesenchymal progenitor cells and primary knee fibroblasts. 11,19 Notably, AdipoRon also improved knee passive extension in a mouse model of knee stiffness. 11,19 Furthermore, it was recently demonstrated that intravenous (IV) AdipoRon administration is safe in surgically stressed rabbits.…”

“…11,19 Notably, AdipoRon also improved knee passive extension in a mouse model of knee stiffness. 11,19 Furthermore, it was recently demonstrated that intravenous (IV) AdipoRon administration is safe in surgically stressed rabbits. 20 However, whether this promising medication with an established safety profile can treat or prevent arthrofibrosis remains to be elucidated through studies in larger animal models of orthopedic diseases.…”