Epigenetic alterations in rotator cuff tendinopathy and degenerative cuff tears: a systematic review

Background: Rotator cuff (RC) tendinopathy and degenerative cuff tears are common, disabling conditions with a complex molecular etiology. Furthermore, RC pathology becomes increasingly common with age, especially in the case of supraspinatus tendon injury. Concurrent with increased RC pathology during aging are epigenetic alterations, which makes the relationship between RC pathology and epigenetic alterations an area of interest. The role of epigenetics in RC pathology is still being elucidated but has potential to provide diagnostic biomarkers and therapeutic targets. We aimed to systematically review the altered epigenetic signatures and mechanisms underlying RC pathology. Methods: Four electronic databases (PubMed, Embase.com, Cochrane, and Google Scholar) were searched 27 August, 2024, for primary studies reporting on epigenetic alterations (DNA methylation, histone modifications, noncoding RNAs) in RC tendinopathy and associated atraumatic cuff tear tissue. Risk of bias and methodological quality of all included studies were assessed according to the Newcastle-Ottawa Scale. Results: Of the 1,190 identified references, 39 studies were included, totaling 464 human and 641 animal model participant shoulders. We identified altered expression of 87 microRNAs, 24 of which were reported on in multiple studies, 62 long noncoding RNAs, 26 circular RNAs, 9 histone modifications or histone-modifying enzymes, and 11 genes exhibiting altered DNA methylation within the disease state. Epigenetic signatures were most commonly associated with inflammation, extracellular matrix degeneration, muscle atrophy, and fatty infiltration. We also report on 15 studies characterizing epigenetic therapeutics (5 microRNA, 1 long noncoding RNA, 3 histone-modifying enzymes, and 6 gene silencing RNA). Conclusion: Our findings indicate that epigenetic regulation may play an important role in the pathophysiology of RC tendinopathy and degenerative tear and that there is a high potential for epigenetic biomarkers and therapeutics to aid in the diagnosis, prognosis, and treatment of this condition.