Genetic Factors in Rotator Cuff Pathology, Part 1

There has been a substantial amount of new research on how the field of genetics is influencing the practice of medicine across disciplines. Prior to becoming a physical therapist, I studied cell and molecular biology at Michigan State University, and I still have a strong interest in genetics and understanding how genetics can influence all aspects of life.

Over the past several years, numerous studies have been published on the influence of a person’s genetic profile on rotator cuff pathology. Recently, more studies have been published on the influence of a patient’s genetic profile on their response to a rotator cuff repair. With the advancement of knowledge of this topic, we published a review paper in the International Journal of Sports Physical Therapy, highlighting the results of these studies.

Current concepts on the genetic factors in rotator cuff pathology and future implications for sports physical therapists 

Travis Orth, PT, DPT, MS, OCS

Jessica Paré, PT, MPT, OCS, SCS

John E. Froehlich, PhD

ABSTRACT

Context: Recent advances within the field of genetics are currently changing many of the methodologies in which medicine is practiced. These advances are also beginning to influence the manner in which physical therapy services are rendered. Rotator cuff pathology is one of the most common diagnoses treated by the sports physical therapist. The purpose of this commentary is to educate sports physical therapists on the recent advances regarding how genetics influences rotator cuff pathology, including rotator cuff tears, and provide a perspective on how this information will likely influence post-operative shoulder rehabilitation in the near future.

Evidence Acquisition: A comprehensive review of the literature was completed using the Medline database along with individual searches of relevant physical therapy, surgical, cell biology, and sports medicine journals. Search terms included: shoulder, rotator cuff pathology, genetics, apoptosis, and physical therapy. Search results were compiled and evaluated; relevant primary studies and review articles were gathered. The results from this comprehensive review are summarized here.

Study Design: Clinical Commentary, Review of the Literature

Results: Recent advances within the understanding of rotator cuff pathology have further elucidated the cellular and molecular mechanisms associated with rotator cuff tears. There appears to be a hypoxic-induced apoptotic cellular pathway that contributes to rotator cuff tears. Activation of specific proteins termed matrix metalloproteinases appear to be involved in not only primary rotator cuff tears, but also may influence the re-tear rate after surgical intervention.

Further advancements in the understanding of the cellular mechanisms contributing to rotator cuff tears and postoperative techniques to help prevent re-tears may soon influence the methodology in which physical therapy services are provided to patients sustaining a rotator cuff injury.

Conclusions: At this time, continued research is required to more fully develop a comprehensive understanding of the role of genetic variables within primary rotator cuff tears as well as their influences on post-operative rehabilitation from rotator cuff repair surgery.

Introduction

A greater understanding of the cellular mechanisms associated with rotator cuff pathology can help a therapist better treat a patient with shoulder pain. Additionally, the recent research on the influence of genetics in post-operative recovery may soon be able to be used to better categorize a patient into an optimal post-operative rehabilitation program to help minimize the chance of complications such as stiffness or re-tearing of the repair. However, further research is required at this point prior to being able to stratify patients according to their genetic profile.

Hereditary Associations of Rotator Cuff Tears

It has been established that close relatives display an increased incidence of rotator cuff tears, which suggests that genetic factors are influencing the presence of rotator cuff pathology and subsequent tears (Harvey, 2004). Interestingly, it has also been shown that spouses also display an increased prevalence of rotator cuff pathology, suggesting an “environmental” factor may also be present, as an individual’s spouse would display a dissimilar genetic profile, but likely engage in similar activities. The interplay between a person’s genetic predisposition and environmental factors appears to play a role in the development and progression of rotator cuff pathology (Nho, 2008).

Apoptotic Driven Rotator Cuff Degeneration

Apoptosis is a highly regulated cellular process that promotes a systematic degeneration of cellular contents to be used elsewhere in the body. This process is also termed programmed cell death, due to the highly regulated cellular signaling involved with this process. Apoptosis is an integral aspect of cellular homeostasis and allows for the proper balance of tissue remodeling and regeneration within the body. However, excessive amounts of apoptosis can result in a deleterious effect to tissue and may result in tissue tearing. It is believed that excessive amounts of apoptosis is involved with rotator cuff tearing (Yuan, 2002).

The poor blood supply of the distal supraspinatus tendon has long been established (Rathbun and McNab, 1970). This poor blood supply promotes a hypoxic environment within the distal supraspinatus tendon, which has recently been shown to promote an upregulation of hypoxic inducible factor 1 alpha (HIF1α) (Vasagiri and Kutala, 2014). Once activated, HIF1α is then hypothesized to promote a Bcl-2 Nineteen kilodalton interacting protein (BNip3) driven Cytochrome C release from the mitochondria, which is then responsible for an intrinsically driven apoptotic response within the distal supraspinatus tendon (Benson, 2010; Lee, 2013) (Figure 1). This apoptotic response may be responsible for rotator cuff tendon tearing, as it has been shown that increased apoptotic tissue is present within the torn edges of a supraspinatus tendon compared to control subscapularis tendon (Yuan, 2002).

It is important for rehabilitation specialists and physicians to have a good understanding of this process in order to efficiently and effectively implement interventions to retard this detrimental process to the rotator cuff tendon. Utilizing physical therapy interventions to promote improved blood flow and open the subacromial space – such as pec minor stretching and parascapular strengthening – in theory should help slow or even prevent an aggressive hypoxic induced apoptotic response within the supraspinatus tendon. Early physical therapy intervention may help prevent the progression of a small or partial rotator cuff tear from progressing to a larger tear that would require surgical intervention.

Benson RT, McDonnell SM, Knowles HJ, Rees et al. Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis. J Bone Joint Surg Br. 2010; 92(3):448-53.

Lee HJ, Kim YS, Ok JH, et al. Apoptosis occurs throughout the diseased rotator cuff. Am J Sports Med. 2013;41(10):2249-55.

Harvie P, Ostlere SJ, Teh J, et al. Genetic influence in the aetiology of tears of the rotator cuff. Sibling risk of a full-thickness tear. J Bone Joint Surg Br. 2004;86(5):696-700.

Nho S, Yadav H, Shindle M K. et al. Basic science update: rotator cuff degeneration: etiology and pathogenesis. Amer J Sports Med. 2008;36(5):987-93.

Rathbun JB, Macnab I. The microvascular pattern of the rotator cuff. J Bone Joint Surg Br. 1970;52(3):540-53.

Vasagiri N, Kutala VK. Structure, function, and epigenetic regulation of BNIP3: a pathophysiological relevance. Mol Biol Rep.2014;41(11):7705-14.

Yuan J, Murrell GA, Wei AQ, et al. Apoptosis in rotator cuff tendonopathy. J Orthop Res. 2002;20(6):1372-9.

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