Approved Research

Identification of genetic variants associated to the pathogenesis of arthrofibrosis after total knee arthroplasty

Lay summary

Arthrofibrosis is a debilitating complication after routine primary TKA with an uncertain etiology. Our research team has established potential pharmacotherapies to prevent and treat arthrofibrosis in a translational animal model. However, not all patients with TKAs develop arthrofibrosis. Therefore, it is clinically desirable, and immediately translatable, to identify patients who are at risk, and thus would benefit most from prophylactic treatment.  Fibrotic disorders in many tissues have genetic causes (e.g. pulmonary, cardiac, and musculoskeletal fibrosis) that are either tissue-specific or converge around a common TGF!-related fibrotic pathway. Similar to these fibrotic disorders, the scientific premise of our study is that arthrofibrosis also has genetic determinants that result in the dysregulation of fibrotic pathways at the cellular level. This application will address the central hypothesis that nucleotide variations in both tissue-specific genes and genes linked to general fibrotic pathways together control formation and repair of connective tissues in articulating joints and that this genetic variation predisposes individuals to arthrofibrosis following surgical insult (e.g., TKA). Our specific aim will examine whether individuals with an arthrofibrotic/pro-fibrotic phenotype will possess predisposing genetic variants associated with the disease phenotype. The key biomedical significance of this study is the establishment that there are definitive genetic determinants which modulate the pathogenesis of arthrofibrosis. The proposed research is both clinically and conceptually innovative because the genetic markers identified here will (i) permit risk stratification for early intervention in specific cohorts of patients, and (ii) provide new insights into disease pathogenesis and potential pharmacological targets in fibrosis-related mechanistic pathways. Such increased understanding of the pathophysiologic and genetic mechanisms behind arthrofibrosis will ultimately permit clinical implementation of a theragnostic approach for this disorder. After receiving the whole exome sequencing and the genotyping data from UK Biobank, analysis and publication will be completed within a 1 year period.