Glycation and Rotator Cuff Degeneration

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Advanced glycation end products (AGEs) form through a nonenzymatic process by which reducing sugars undergo Maillard rearrangement with amino acids. During rearrangement, the carbonyl group of the sugar reacts with the amino group of the amino acid, producing N-substituted glycosylamine and water.

During cooking, glycation occurs at 140° to 165° C (280° to 330° F), resulting in the browning of foods such as bread and French fries. This nonenzymatic reaction also occurs at human body temperature over decades. AGE formation can decrease the viscoelasticity and tensile strength of human tissue, resulting in increased mechanical stiffness that affects bone, ligaments, cartilage, and menisci. In cartilage, the excessive accumulation of AGEs leads to a more brittle matrix that is susceptible to fatigue and failure. AGEs also contribute to the etiology of several diabetic complications, including adhesive capsulitis of the shoulder.

Rotator cuff degeneration and tears become more common with age. Accumulated mechanical loads and anatomic variation play a large role. The role of AGEs in rotator cuff degeneration and tears has been suspected, but the exact mechanisms remain in question. Investigators recently showed that AGEs have detrimental effects on human rotator cuff-derived cells in vitro and on intact rat infraspinatus tendons ex vivo.¹

In Vitro Findings
Rotator cuff-derived cells were obtained from 12 torn cuff edges during supraspinatus tendon repairs in patients with an average age 64.8 years. The cells were cultured in (1) regular medium with 500 μg/mL AGEs (high-AGE group), (2) regular medium with 100 μg/mL AGEs (low-AGE group), and (3) regular medium alone (control group). Cell viability was significantly suppressed in the high-AGE group relative to the control group. Vascular endothelial growth factor secretion was significantly greater in the high- and low-AGE groups than in the control group. Immunofluorescence stain demonstrated enhancement of hypoxia-inducible factor-1α, reactive oxygen species expressions, and cell apoptosis in the high- and low-AGE groups compared with the control group.

Ex Vivo Findings
Four upper limbs with intact rotator cuff tendons were harvested from 10-week old rats and cultured in regular medium or regular medium with 500 μg/mL AGEs. Mechanical testing showed significantly higher tensile strength in the control group than in the AGE group.

These results beg the question as to whether reduction of AGEs might delay or prevent rotator cuff senescence-related degeneration.

Reference

1. Mifune Y, Inui A, Muto T, Nishimoto H, Kataoka T, Kurosawa T, Yamaura K, Mukohara S, Niikura T, Kokubu T, Kuroda R. Influence of advanced glycation end products on rotator cuff. J Shoulder Elbow Surg. 2019 Aug;28(8):1490-1496. doi: 10.1016/j.jse.2019.01.022. Epub 2019 Apr 10. PMID: 30981546