Diabetes mellitus (DM) is associated with musculoskeletal complications—including tendon dysfunction and injury. Patients with DM show altered foot and ankle mechanics that have been attributed to tendon dysfunction as well as impaired recovery post-tendon injury. Despite the problem of DM-related tendon complications, treatment guidelines specific to this population of individuals are lacking. DM impairs tendon structure, function, and healing capacity in tendons throughout the body, but the Achilles tendon is of particular concern and most studied in the diabetic foot. At macroscopic levels, asymptomatic, diabetic Achilles tendons may show morphological abnormalities such as thickening, collagen disorganization, and/or calcific changes at the tendon enthesis. At smaller length scales, DM affects collagen sliding and discrete plasticity due to glycation of collagen. However, how these alterations translate to mechanical deficits observed at larger length scales is an area of continued investigation. In addition to dysfunction of the extracellular matrix, tendon cells such as tenocytes and tendon stem/progenitor cells show significant abnormalities in proliferation, apoptosis, and remodeling capacity in the presence of hyperglycemia and advanced glycation end-products, thus contributing to the disruption of tendon homeostasis and healing. Improving our understanding of the effects of DM on tendons—from molecular pathways to patients—will progress toward targeted therapies in this group at high risk of foot and ankle morbidity.
more »
« less
Human Achilles tendon mechanical behavior is more strongly related to collagen disorganization than advanced glycation end-products content
Abstract Diabetes is associated with impaired tendon homeostasis and subsequent tendon dysfunction, but the mechanisms underlying these associations is unclear. Advanced glycation end-products (AGEs) accumulate with diabetes and have been suggested to alter tendon function. In vivo imaging in humans has suggested collagen disorganization is more frequent in individuals with diabetes, which could also impair tendon mechanical function. The purpose of this study was to examine relationships between tendon tensile mechanics in human Achilles tendon with accumulation of advanced glycation end-products and collagen disorganization. Achilles tendon specimens (n = 16) were collected from individuals undergoing lower extremity amputation or from autopsy. Tendons were tensile tested with simultaneous quantitative polarized light imaging to assess collagen organization, after which AGEs content was assessed using a fluorescence assay. Moderate to strong relationships were observed between measures of collagen organization and tendon tensile mechanics (range of correlation coefficients: 0.570–0.727), whereas no statistically significant relationships were observed between AGEs content and mechanical parameters (range of correlation coefficients: 0.020–0.210). Results suggest that the relationship between AGEs content and tendon tensile mechanics may be masked by multifactorial collagen disorganization at larger length scales (i.e., the fascicle level).
more »
« less
- Award ID(s):
- 2037125
- PAR ID:
- 10316974
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 11
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Quantitative magnetic resonance imaging (qMRI) measures have provided insights into the composition, quality, and structure‐function of musculoskeletal tissues. Low signal‐to‐noise ratio has limited application to tendon. Advances in scanning sequences and sample positioning have improved signal from tendon allowing for evaluation of structure and function. The purpose of this study was to elucidate relationships between tendon qMRI metrics (T1, T2, T1ρ and diffusion tensor imaging [DTI] metrics) with tendon tissue mechanics, collagen concentration and organization. Sixteen human Achilles tendon specimens were collected, imaged with qMRI, and subjected to mechanical testing with quantitative polarized light imaging. T2 values were related to tendon mechanics [peak stress (rsp = 0.51,p = 0.044), equilibrium stress (rsp = 0.54,p = 0.033), percent relaxation (rsp = −0.55,p = 0.027), hysteresis (rsp = −0.64,p = 0.007), linear modulus (rsp = 0.67,p = 0.009)]. T1ρ had a statistically significant relationship with percent relaxation (r = 0.50,p = 0.048). Collagen content was significantly related to DTI measures (range ofr = 0.56–0.62). T2 values from a single slice of the midportion of human Achilles tendons were strongest predictors of tendon tensile mechanical metrics. DTI diffusivity indices (mean diffusivity, axial diffusivity, radial diffusivity) were strongly correlated with collagen content. These findings build on a growing body of literature supporting the feasibility of qMRI to characterize tendon tissue and noninvasively measure tendon structure and function. Statement of Clinical Significance: Quantitative MRI can be applied to characterize tendon tissue and is a noninvasive measure that relates to tendon composition and mechanical behavior.more » « less
-
Diabetic retinopathy is a complex, microvascular disease that impacts millions of working adults each year. High blood glucose levels from Diabetes Mellitus lead to the accumulation of advanced glycation end-products (AGEs), which promote inflammation and the breakdown of the inner blood retinal barrier (iBRB), resulting in vision loss. This study used an in vitro model of hyperglycemia to examine how endothelial cells (ECs) and Müller glia (MG) collectively regulate molecular transport. Changes in cell morphology, the expression of junctional proteins, and the reactive oxygen species (ROS) of ECs and MG were examined when exposed to a hyperglycemic medium containing AGEs. Trans-endothelial resistance (TEER) assays were used to measure the changes in cell barrier resistance in response to hyperglycemic and inflammatory conditions, with and without an anti-VEGF compound. Both of the cell types responded to hyperglycemic conditions with significant changes in the cell area and morphology, the ROS, and the expression of the junctional proteins ZO-1, CX-43, and CD40, as well as the receptor for AGEs. The resistivities of the individual and dual ECs and MG barriers decreased within the hyperglycemia model but were restored to that of basal, normoglycemic levels when treated with anti-VEGF. This study illustrated significant phenotypic responses to an in vitro model of hyperglycemia, as well as significant changes in the expression of the key proteins used for cell–cell communication. The results highlight important, synergistic relationships between the ECs and MG and how they contribute to changes in barrier function in combination with conventional treatments.more » « less
-
Rotator cuff pathology is a common musculoskeletal condition that disproportionately affects older adults, as well as patients with diabetes mellitus and chronic kidney disease. It is known that increased age and kidney dysfunction have been correlated to acidotic states, which may be related to the increased incidence of rotator cuff injury. In order to investigate the potential relationship between acidosis and rotator cuff composition and mechanics, this study utilizes a 14-day murine model of metabolic acidosis and examines the effects on the supraspinatus tendon-humeral head attachment complex. The elastic matrix in the enthesis exhibited significant changes beginning at day 3 of acidosis exposure. At day 3 and day 7 timepoints, there was a decrease in collagen content seen in both mineralized and unmineralized tissue as well as a decrease in mineral:matrix ratio. There is also evidence of both mineral dissolution and reprecipitation as buffering ions continually promote pH homeostasis. Mechanical properties of the tendon-to-bone attachment were studied; however, no significant changes were elicited in this 14-day model of acidosis. These findings suggest that acidosis can result in significant changes in enthesis composition over the course of 14 days; however, enthesis mechanics may be more structurally mediated rather than affected by compositional changes.more » « less
-
Diabetic retinopathy is a leading cause of vision loss in working adults, with disproportionate impact on women with lowered estrogen. Sex hormones and their receptors are significant to neuroprotection of the inner blood-retinal barrier (iBRB), a tissue that regulates transport across the neuroretina and vasculature. Moreover, high glucose levels in diabetes lead to the formation of advanced glycation end products (AGEs), which promote inflammation and iBRB breakdown to result in vision loss. This study examined the effects of supplemental estradiol on cell reactivity and cell barrier resistance within an in vitro model of hyperglycemia. Changes in morphology and expression of reactive oxygen species were examined when cells were exposed to a hyperglycemic medium containing AGEs, with and without supplemental estradiol. Cell morphology was assessed via changes in cell area and cell shape index, while intracellular ROS levels were measured using a ROS-sensitive dye. In addition, trans endothelial resistance (TEER) assays were used to measure changes in cell barrier function in response to hyperglycemic conditions, with and without supplemental estradiol. Results show that ROS levels in Müller glia in hyperglycemic conditions significantly decreased in response to supplemental estradiol. The estradiol further increased the resistivity of Müller glia and endothelial cell barriers cultured in high glucose and AGEs. This project illustrates the restorative effects of estradiol in collective responses of cell barriers formed by endothelial cells and Müller glia.more » « less
An official website of the United States government

