Page 22 - ISAKOS Newsletter 2016 Volume 1

CURRENT CONCEPTS
Genetics and Pathogenesis of Rotator Cuff Healing: The Race is Long!
The modulation of the tissue microenvironment through cell or gene therapy, as well as with the use of tissue scaffolds, may also provide promising options for the future. A recent study used ultrasound-guided human umbilical cord blood (UCB)-derived mesenchymal stem cell (MSC) injection to regenerate a full-thickness subscapularis tendon tear in a rabbit model without surgical repair or bioscaffold. The histology analysis revealed that UCB-derived MSCs was able to induce regeneration of rotator cuff tendon tear and that the regenerated tissue was predominantly composed of type I collagen. It is important to highlight that it is still necessary to optimize these methods prior clinical use.
Genetic factors have been suggested as intrinsic risk factors for rotator cuff tendon injury. Harvie et al described that siblings present an increased risk for full-thickness tears and of experiencing symptoms than spouses, who were not biologically related. Moreover, Gwilym et al reported that full-thickness rotator cuff tears in siblings are more likely to progress over a period of five years than in a control population. Thus, these studies showed that genetic factors may have an important role in the susceptibility and the progression of rotator cuff tears.
It is believed that the etiology of the rotator cuff tear is determined by both genetic and environmental factors (for example, smoking habit and type of work). Degenerative rotator cuff tear is seen as a multifactorial trait, in which the interaction of several genetic and environmental factors is necessary for the disease development.
It is of interest to elucidate the genetic variants (also called as DNA polymorphisms) that may be responsible for interindividual susceptibility to rotator cuff tears. The first study in this field investigated whether some polymorphisms within specific genes involved in intrinsic tendon-muscle degeneration were associated with the risk of rotator cuff disease, including tendinosis, partial-thickness cuff tear, and full-thickness cuff tear. The study performed by Motta et al. showed association of this disease and some genetic variants of DEFB1, ESRRB, FGF3, FGF10 and FGFR1 genes in the Brazilian population. Terrlink et al performed an independent study aiming to confirm the association between these multiple candidate genes and rotator cuff disease in a U.S. patient’s cohort. The authors demonstrated that two variants in ESRRB gene were associated with the risk of rotator cuff disease. More recently, this research group performed the first genome-wide study trying to screen genetic factors influencing rotator cuff tearing. Two polymorphisms were significantly associated, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis.
Our group has also been studying this topic (unpublished data). We firstly detected that several genes involved in the synthesis and repair of the extracellular matrix presented altered expression in human injured supraspinatus tendon samples, such as, Type V collagen (COL5A1, a collagen involved in the fibrinogenesis process). We are trying to determine whether polymorphisms of these genes may be associated with risk of rotator cuff injury. Among the preliminary findings, a polymorphism in COL5A1 was associated with risk of rotator cuff injury.
Few genetic variants that are involved in susceptibility for rotator cuff tears have been identified. Understanding of these genetic factors, as well as their interactions with environmental factors, is necessary to better understand the disease etiology and to allow for personalized medicine. The development of an accurate prediction model based on these factors may help in the identification of individuals at risk for the development of rotator cuff tear and in the selection of treatment and prevention strategies.
In summary, the process of healing is still an issue to be studied since re-tear rates are very high. Surgeons may potentially improve outcomes after rotator cuff repair by controlling and optimizing the mechanical and biological environment after rotator cuff repair. However, the scientific literature regarding the best choice for augmentation remains unclear. Current evidence is not sufficient to conclude that PRP provides clear clinical benefit and augmentation of soft tissue healing. Although PRP seems to present great potential, there is a lack of standardization and the ideal platelet concentrations, dose-response curves, saturation effects and ideal timing of intervention remain unknown. The potential of exogenous cells sources to improve healing combined with PRP may be of interest in the future. Also we are making an effort to advance the knowledge regarding the contributions of genetics in this area.
20 ISAKOS NEWSLETTER 2016: Volume I