The Role of Epigenomics in Mapping Potential Precursors for Foot and Ankle Tendinopathy: A Systematic Review

Tendinopathy of the foot and ankle is a common clinical problem for which the exact etiology is poorly understood. The field of epigenetics has been a recent focus of this investigation. The purpose of this article was to review the genomic advances in foot and ankle tendinopathy that could potentially be used to stratify disease risk and create preventative or therapeutic agents. A multi-database search of PubMed, Cochrane, Google Scholar, and clinicaltrials.gov from January 1, 2000 to July 1, 2022 was performed. A total of 18 articles met inclusion and exclusion criteria for this review. The majority of such research utilized case-control candidate gene association to identify different genetic risk factors associated with chronic tendinopathy. Polymorphisms in collagen genes COL5A1, COL27A1, and COL1A1 were noted at a significantly higher frequency in Achilles tendinopathy versus control groups. Other allelic variations that were observed at an increased incidence in Achilles tendinopathy were TNC and CASP8. The extracellular matrix (ECM) demonstrated macroscopic changes in Achilles tendinopathy, including an increase in aggrecan and biglycan mRNA expression, and increased expression of multiple matrix metalloproteinases. Cytokine expression was also influenced in pathology and aberrantly demonstrated dynamic response to mechanical load. The pathologic accumulation of ECM proteins and cytokine expression alters the adaptive response normal tendon has to physiologic stress, further propagating the risk for tendinopathy. By identifying and understanding the epigenetic mediators that lead to tendinopathy, therapeutic agents can be developed to target the exact underlying etiology and minimize side effects.

Automated summary

Tendinopathy of the foot and ankle remains a poorly understood clinical problem. This article reviewed genomic advances in understanding the disease and its potential application in risk stratification and development of preventative or therapeutic agents. The research identified genetic risk factors, such as collagen gene polymorphisms, associated with chronic tendinopathy. Changes in the extracellular matrix and cytokine expression were also observed, which contribute to the pathology of tendinopathy. By targeting the underlying epigenetic mediators, therapeutic interventions can be developed to minimize side effects.