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Molecular pathology of human knee arthrofibrosis defined by RNA sequencing.

ABSTRACT: Arthrofibrosis is an abnormal histopathologic response, is debilitating for patients, and poses a substantial unsolved clinical challenge. This study characterizes molecular biomarkers and regulatory pathways associated with arthrofibrosis by comparing fibrotic and non-fibrotic human knee tissue. The fibrotic group encompasses 4 patients undergoing a revision total knee arthroplasty (TKA) for arthrofibrosis (RTKA-A) while the non-fibrotic group includes 4 patients undergoing primary TKA for osteoarthritis (PTKA) and 4 patients undergoing revision TKA for non-arthrofibrotic and non-infectious etiologies (RTKA-NA). RNA-sequencing of posterior capsule specimens revealed differences in gene expression between each patient group by hierarchical clustering, principal component analysis, and correlation analyses. Multiple differentially expressed genes (DEGs) were defined in RTKA-A versus PTKA patients (i.e., 2059 up-regulated and 1795 down-regulated genes) and RTKA-A versus RTKA-NA patients (i.e., 3255 up-regulated and 3683 down-regulated genes). Our findings define molecular and pathological markers of arthrofibrosis, as well as novel potential targets for risk profiling, early diagnosis and pharmacological treatment of patients.

SUBMITTER: Bayram B

PROVIDER: S-EPMC7217749 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Molecular Pathology of Human Knee Arthrofibrosis Defined by RNA Sequencing

Project description:This study aims to compare the genetic profile of fibrotic and non-fibrotic human knee capsular tissue in an effort to identify possible molecular pathways responsible for the development of AF. RNA sequencing (RNA-seq) and bioinformatics were used to define differentially expressed genes (DEGs) and molecular pathways linked to joint stiffening. Gene expression profiling revealed a distinct clustering of each patient group by principal component analysis, hierarchical clustering and similarity matrix analysis. Three prospectively-collected, matched patient cohorts were used to formally describe gene expression signatures of AF patients. The findings define molecular and pathological markers of AF, as well as novel potential targets for pre-diagnosis and pharmacological treatment of AF patients.

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Molecular Pathology of Human Knee Arthrofibrosis Defined by RNA Sequencing

Project description:Molecular Pathology of Human Knee Arthrofibrosis Defined by RNA Sequencing

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Human xylosyltransferases--mediators of arthrofibrosis? New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy.

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A potential mode of action for Anakinra in patients with arthrofibrosis following total knee arthroplasty.

Project description:Arthrofibrosis is a fibroproliferative disease characterised by excessive deposition of extracellular matrix components intra-articularly leading to pain and restricted range of movement. Although frequently observed following total knee arthroplasty (TKA) no therapeutic options exist. A pilot study demonstrated that intra-articular injection of Anakinra, an IL-1R antagonist, improved range of movement and pain in patients with arthrofibrosis however the mechanism of action is unknown. We hypothesise that IL-1?/? will drive an inflammatory phenotype in fibroblasts isolated from the knee, therefore identifying a potential mechanism of action for Anakinra in arthrofibrosis following TKA. Fibroblasts isolated from synovial membranes and infra-patellar fat pad of patients undergoing TKA express high levels of IL-1R1. Stimulation with IL-1?/? induced a pro-inflammatory phenotype characterised by increased secretion of GMCSF, IL-6 and IL-8. No significant difference in the inflammatory response was observed between fibroblasts isolated from synovial membrane or infra-patellar fat pad. IL-1?/? treatments induced a pro-inflammatory phenotype in fibroblasts from both synovial membrane and infra-patellar fat pad and therefore Anakinra can likely have an inhibitory effect on fibroblasts present in both tissues in vivo. It is also likely that fibroblast responses in the tissues are controlled by IL-1?/? availability and not their ability to respond to it.

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Identification of novel biomarkers for arthrofibrosis after total knee arthroplasty in animal models and clinical patients.

Project description:BackgroundArthrofibrosis is a debilitating complication after total knee arthroplasty (TKA) which becomes a considerable burden for both patients and clinical practitioners. Our study aimed to identify novel biomarkers and therapeutic targets for drug discovery.MethodsPotential biomarker genes were identified based on bioinformatic analysis. Twelve male New Zealand white rabbits underwent surgical fixation of unilateral knees to mimics the joint immobilization of the clinical scenario after TKA surgery. Macroscopic assessment, hydroxyproline content determination, and histological analysis of tissue were performed separately after 3-days, 1-week, 2-weeks, and 4-weeks of fixation. We also enrolled 46 arthrofibrosis patients and 92 controls to test the biomarkers. Clinical information such as sex, age, range of motion (ROM), and visual analogue scale (VAS) was collected by experienced surgeons FINDINGS: Base on bioinformatic analysis, transforming growth factor-beta receptor 1 (TGFBR1) was identified as the potential biomarkers. The level of TGFBR1 was significantly raised in the rabbit synovial tissue after 4-weeks of fixation (p<0.05). TGFBR1 also displayed a highly positive correlation with ROM loss and hydroxyproline contents in the animal model. TGFBR1 showed a significantly higher expression level in arthrofibrosis patients with a receiver operating characteristic (ROC) area under curve (AUC) of 0.838. TGFBR1 also performed positive correlations with VAS baseline (0.83) and VAS after 1 year (0.76) while negatively correlated with ROM baseline (-0.76) in clinical patients.InterpretationOur findings provided novel biomarkers for arthrofibrosis diagnosis and uncovered the role of TGFBR1. This may contribute to arthrofibrosis prevention and therapeutic drug discovery.FundingNone.

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Project description:Arthrofibrosis is a common, but often overlooked, condition that imparts significant morbidity following injuries and surgery to the foot and ankle. The most common etiologies are related to soft tissue trauma with subsequent fibrotic and contractile scar tissue formation within the ligaments and capsule of the ankle. This leads to pain, alterations in gait, and ankle dysfunction. Initial treatment often includes extensive physical therapy, however, if severe enough surgical options exist. Although the literature regarding ankle arthrofibrosis is scarce, this review article provides a greater understanding of the pathogenesis of arthrofibrosis and describes the current and future therapeutic options to treat fibrotic joints. Level of Evidence: Level V, expert opinion.

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