Abstract:Tendons heal by fibrosis, which hinders function and increases re-injury risk. Yet the biology that leads to degeneration and regeneration of tendons is not completely understood. Improved understanding of the metabolic nuances that cause diverse outcomes in tendinopathies is required to solve these problems. ‘Omics methods are increasingly used to characterize phenotypes in tissues. Multiomics integrates ‘omic datasets to identify coherent relationships and provide insight into differences in molecular and me… Show more
“…Rotator cuff injuries affect 30% of people over the age of 60, leading to over 600,000 repairs each year in the U.S. (Vitale et al, 2007;Dang and Davies, 2018). Despite their critical musculoskeletal functions, tendons lack the ability to regenerate when injured (Arya and Kulig, 2010;Helland et al, 2013;Derwin and Thomopoulos, 2020;Sarmiento and Little, 2021). Tendons are also commonly associated with heritable connective tissue disorders and birth abnormalities, including Ehlers-Danlos syndrome (EDS) and clubfoot (Browne, 1931;Windisch et al, 2007;Gazit et al, 2016).…”
Tendon mechanical properties are significantly compromised in adult tendon injuries, tendon-related birth defects, and connective tissue disorders. Unfortunately, there currently is no effective treatment to restore native tendon mechanical properties after postnatal tendon injury or abnormal fetal development. Approaches to promote crosslinking of extracellular matrix components in tendon have been proposed to enhance insufficient mechanical properties of fibrotic tendon after healing. However, these crosslinking agents, which are not naturally present in the body, are associated with toxicity and significant reductions in metabolic activity at concentrations that enhance tendon mechanical properties. In contrast, we propose that an effective method to restore tendon mechanical properties would be to promote lysyl oxidase (LOX)-mediated collagen crosslinking in tendon during adult tissue healing or fetal tissue development. LOX is naturally occurring in the body, and we previously demonstrated LOX-mediated collagen crosslinking to be a critical regulator of tendon mechanical properties during new tissue formation. In this study, we examined the effects of recombinant LOX treatment on tendon at different stages of development. We found that recombinant LOX treatment significantly enhanced tensile and nanoscale tendon mechanical properties without affecting cell viability or collagen content, density, and maturity. Interestingly, both tendon elastic modulus and LOX-mediated collagen crosslink density plateaued at higher recombinant LOX concentrations, which may have been due to limited availability of adjacent lysine residues that are near enough to be crosslinked together. The plateau in crosslink density at higher concentrations of recombinant LOX treatments may have implications for preventing over-stiffening of tendon, though this requires further investigation. These findings demonstrate the exciting potential for a LOX-based therapeutic to enhance tendon mechanical properties via a naturally occurring crosslinking mechanism, which could have tremendous implications for an estimated 32 million acute and chronic tendon and ligament injuries each year in the U.S.
“…Rotator cuff injuries affect 30% of people over the age of 60, leading to over 600,000 repairs each year in the U.S. (Vitale et al, 2007;Dang and Davies, 2018). Despite their critical musculoskeletal functions, tendons lack the ability to regenerate when injured (Arya and Kulig, 2010;Helland et al, 2013;Derwin and Thomopoulos, 2020;Sarmiento and Little, 2021). Tendons are also commonly associated with heritable connective tissue disorders and birth abnormalities, including Ehlers-Danlos syndrome (EDS) and clubfoot (Browne, 1931;Windisch et al, 2007;Gazit et al, 2016).…”
Tendon mechanical properties are significantly compromised in adult tendon injuries, tendon-related birth defects, and connective tissue disorders. Unfortunately, there currently is no effective treatment to restore native tendon mechanical properties after postnatal tendon injury or abnormal fetal development. Approaches to promote crosslinking of extracellular matrix components in tendon have been proposed to enhance insufficient mechanical properties of fibrotic tendon after healing. However, these crosslinking agents, which are not naturally present in the body, are associated with toxicity and significant reductions in metabolic activity at concentrations that enhance tendon mechanical properties. In contrast, we propose that an effective method to restore tendon mechanical properties would be to promote lysyl oxidase (LOX)-mediated collagen crosslinking in tendon during adult tissue healing or fetal tissue development. LOX is naturally occurring in the body, and we previously demonstrated LOX-mediated collagen crosslinking to be a critical regulator of tendon mechanical properties during new tissue formation. In this study, we examined the effects of recombinant LOX treatment on tendon at different stages of development. We found that recombinant LOX treatment significantly enhanced tensile and nanoscale tendon mechanical properties without affecting cell viability or collagen content, density, and maturity. Interestingly, both tendon elastic modulus and LOX-mediated collagen crosslink density plateaued at higher recombinant LOX concentrations, which may have been due to limited availability of adjacent lysine residues that are near enough to be crosslinked together. The plateau in crosslink density at higher concentrations of recombinant LOX treatments may have implications for preventing over-stiffening of tendon, though this requires further investigation. These findings demonstrate the exciting potential for a LOX-based therapeutic to enhance tendon mechanical properties via a naturally occurring crosslinking mechanism, which could have tremendous implications for an estimated 32 million acute and chronic tendon and ligament injuries each year in the U.S.
“…Metabolomics and proteomics are sensitive trace analysis methods that allow rapid and simultaneous detection of multiple substances by applying small volumes of bodily fluids [7]. They were more commonly used in molecular research and had advantages in analyzing the microenvironment of the organism [8]. It could provide more detailed mechanistic information.…”
This study aimed to explore the clinical practice of phospholipid metabolic pathways in COVID-19. In this study, 48 COVID-19 patients and 17 healthy controls were included. Patients were divided into mild (n=40) and severe (n=8) according to their severity. Phospholipid metabolites, TCA circulating metabolites, eicosanoid metabolites, and closely associated enzymes and transfer proteins were detected in the plasma of all individuals using metabolomics and proteomics assays, respectively. 30 of the 33 metabolites found differed significantly (P<0.05) between patients and healthy controls (P<0.05), with D-dimmer significantly correlated with all of the lysophospholipid metabolites (LysoPE, LysoPC, LysoPI and LPA). In particular, we found that phosphatidylinositol (PI) and phosphatidylcholine (PC) could identify patients from healthy controls (AUC 0.771 and 0.745, respectively) and that the severity of the patients could be determined (AUC 0.663 and 0.809, respectively). The last measurement before discharge also revealed significant changes in both PI and PC. For the first time, our study explores the significance of the phospholipid metabolic system in COVID-19 patients. Based on molecular pathway mechanisms, three important phospholipid pathways related to Ceramide-Malate acid (Cer-SM), Lysophospholipid (LPs), and membrane function were established. Clinical values discovered included the role of Cer in maintaining the inflammatory internal environment, the modulation of procoagulant LPA by upstream fibrinolytic metabolites, and the role of PI and PC in predicting disease aggravation.
“…33 An enhanced understanding of regional transcriptional and functional heterogeneity in tendon is important to improve our understanding of the underlying molecular signals that dictate the structure and function of tendon, and this is ultimately necessary to inform targeted use of regenerative medicine and tissue engineering therapies. 37 Therefore, the purpose of this study was to develop a regional transcriptomic atlas of Achilles tendons and evaluate the relationship between region-specific gene expression signatures and mechanical properties in an animal model. We hypothesized that the distal tendon region would have increased stiffness compared with the other 2 regions, with a corresponding increase in the expression of collagen and noncollagen ECM genes.…”
Background: Previous studies have examined the transcriptomes and mechanical properties of whole tendons in different regions of the body. However, less is known about these characteristics within a single tendon. Purpose: To develop a regional transcriptomic atlas and evaluate the region-specific mechanical properties of Achilles tendons. Study Design: Descriptive laboratory study. Methods: Achilles tendons from 2-month-old male Sprague Dawley rats were used. Tendons were isolated and divided into proximal, middle, and distal thirds for RNA sequencing (n = 5). For mechanical testing, the Achilles muscle-tendon-calcaneus unit was mounted in a custom-designed materials testing system with the unit clamped over the musculotendinous junction (MTJ) and the calcaneus secured at 90° of dorsiflexion (n = 9). Tendons were stretched to 20 N at a constant speed of 0.0167 mm/s. Cross-sectional area, strain, stress, and Young modulus were determined in each tendon region. Results: An open-access, interactive transcriptional atlas was generated that revealed distinct gene expression signatures in each tendon region. The proximal and distal regions had the largest differences in gene expression, with 2596 genes significantly differentially regulated at least 1.5-fold ( q < .01). The proximal tendon displayed increased expression of genes resembling a tendon phenotype and increased expression of nerve cell markers. The distal region displayed increases in genes involved in extracellular matrix synthesis and remodeling, immune cell regulation, and a phenotype similar to cartilage and bone. There was a 3.72-fold increase in Young modulus from the proximal to middle region ( P < .01) and an additional 1.34-fold increase from the middle to distal region ( P = .027). Conclusion: Within a single tendon, there are region-specific transcriptomic signatures and mechanical properties, and there is likely a gradient in the biological and functional phenotype from the proximal origin at the MTJ to the distal insertion at the enthesis. Clinical Relevance: These findings improve our understanding of the underlying biological heterogeneity of tendon tissue and will help inform the future targeted use of regenerative medicine and tissue engineering strategies for patients with tendon disorders.
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