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

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty-six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K-wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16-week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10-week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose-dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals.

AdipoRon reduces TGFß1-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 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 TGFß1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFß1-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.

A Black feminist youth participatory action research photovoice exploration of Black girls and college women.

Utilizing a Black and Hip Hop feminist and Black girlhood studies theoretical lens, the purpose of this study is to explore how Black girls (14-17) and women (19-22), who are in a youth participatory action research (YPAR) mentoring program, BlackGirlsResearch (pseudonym) express their gendered racial identities and gendered racial experiences through their participation in a YPAR photovoice program. This study seeks to answer the following research question: (1) How do Black girls and college women conceptualize their gendered racial identities and gendered racial lived experiences in predominately white schools using a YPAR methodology and photovoice? Employing a qualitative thematic analysis to explore 36 photovoice narratives, results yielded 3 themes: (1) experiencing challenges at predominately white institutions (PWIs): false inclusivity, continued underrepresentation, and tokenism (2) identifying as "queens of culture": identity and empowerment through art, culture, and breaking conformity and (3) activism, inclusion, and accountability: solutions for PWIs. The results of this study indicate that Black girls and women can not only identify and critically discuss issues related to Black girls and women within PWIs, but through YPAR, they can push for positive youth development and community solutions related to those issues.

Nonsteroidal Anti-Inflammatory Drugs and Oral Corticosteroids Mitigated the Risk of Arthrofibrosis After Total Knee Arthroplasty.

BACKGROUND: The role of medications to prevent arthrofibrosis following total knee arthroplasty (TKA) remains unclear. We investigated the effect of common oral medications with reported antifibrotic properties on preventing arthrofibrosis and manipulation under anesthesia (MUA) following primary TKA. METHODS: Using our total joint registry, 9,771 patients (12,735 knees) who underwent TKA with cemented, posterior-stabilized, and metal-backed tibial components from 2000 to 2016 were identified. Arthrofibrosis, defined as range of motion (ROM) ≤90° for ≥12 weeks postoperatively or as ROM ≤90° requiring MUA, was diagnosed in 454 knees (4%) and matched 1:2 to controls. Mean age was 62 years (range, 19 to 87) and 57% were women. The majority of operative diagnoses were osteoarthritis. Perioperative use of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARBs), oral corticosteroids, antihistamines, and nonsteroidal anti-inflammatory drugs (NSAIDs) were manually confirmed. Medication effect in preventing arthrofibrosis and MUA was assessed using adjusted multivariable analyses. Mean follow-up was 8 years (range, 2 to 20). RESULTS: Reduced risk of arthrofibrosis was associated with perioperative NSAID use (odds ratio (OR) 0.67, P = .045). A similar trend was observed with perioperative corticosteroids (OR 0.52, P = .098). Corticosteroids were associated with reduced risk of MUA (OR 0.26, P = .036), and NSAIDs trended towards reducing MUA (OR 0.69, P = .11). CONCLUSION: This investigation determined that perioperative NSAID use was associated with reduced risk of arthrofibrosis and trended towards reduced risk of subsequent MUA. Similarly, oral corticosteroids were associated with reduced risk of MUA and trended towards reduced risk of arthrofibrosis.

The Safety of Adiponectin Receptor Agonist AdipoRon in a Rabbit Model of Arthrofibrosis.

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with numerous reported physiological benefits in murine models of human disease, including a proposed reduction in fibrosis. However, AdipoRon has never been investigated in rabbits, which provide a robust model for orthopedic conditions. We examined the safety of intravenous (IV) AdipoRon in New Zealand White (NZW) female rabbits surgically stressed by a procedure that mimics human arthrofibrosis. Fifteen female NZW rabbits were prospectively studied using increasing AdipoRon doses based on established literature. AdipoRon was dissolved in dimethyl sulfoxide (DMSO), diluted in normal saline, and administered IV preoperatively and for 5 subsequent days postoperatively. The primary outcome was overall toxicity to rabbits, whereas secondary outcomes were change in rabbit weights and hemodynamics and defining acid-base characteristics of the drug formulation. Two rabbits expired during preoperative drug administration at 25 mg/kg. Remaining rabbits received preoperative doses of DMSO (vehicle), 2.5, 5, or 10 mg/kg of AdipoRon without complications. On postoperative day 1, one rabbit sustained a tonic-clonic seizure after their second dose of 10 mg/kg AdipoRon. The remaining 12 rabbits (4 in each group) received six serial doses of vehicle, 2.5, or 5 mg/kg of AdipoRon without adverse effects. All formulations of AdipoRon were within safe physiological pH ranges (4-5). We are the first to report the use of IV AdipoRon in a surgically stressed rabbit model of orthopedic disease. AdipoRon doses of 5 mg/kg or less appear to be well-tolerated in female NZW rabbits. Impact statement We provided the first in vivo toxicity assessment and dose optimization of a new antifibrotic experimental medication, AdipoRon, in a surgically stressed rabbit model of knee arthrofibrosis.