Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

Freedman, Benjamin R.; Adu-Berchie, Kwasi; Barnum, Carrie E.; Fryhofer, George W.; Salka, Nabeel; Shetye, Snehal S.

doi:10.1002/jor.25251

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Inflammatory cytokines activate numerous signalling cascades including c-Jun N-terminal kinase (JNK), mitogen-activated protein kinases (MAPKs), nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription (STATs) in musculoskeletal cell types (Tsai et al 2014 ; McClellan et al 2019a , b ; Wang et al 2019 ; Freedman et al 2022 ). Furthermore, several animal models have implicated these inflammatory signalling pathways within tendon extracellular matrix interactions (Gupta et al 2010 ; Schwartz et al 2015 ; Abraham et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell–derived factors

et al. 2022

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Tendon injuries occur commonly in both human and equine athletes, and poor tendon regeneration leads to functionally deficient scar tissue and an increased frequency of re-injury. Despite evidence suggesting inadequate resolution of inflammation leads to fibrotic healing, our understanding of the inflammatory pathways implicated in tendinopathy remains poorly understood, meaning successful targeted treatments are lacking. Here, we demonstrate IL-1β, TNFα and IFN-γ work synergistically to induce greater detrimental consequences for equine tenocytes than when used individually. This includes altering tendon associated and matrix metalloproteinase gene expression and impairing the cells’ ability to contract a 3-D collagen gel, a culture technique which more closely resembles the in vivo environment. Moreover, these adverse effects cannot be rescued by direct suppression of IL-1β using IL-1RA or factors produced by BM-MSCs. Furthermore, we provide evidence that NF-κB, but not JNK, P38 MAPK or STAT 1, is translocated to the nucleus and able to bind to DNA in tenocytes following TNFα and IL-1β stimulation, suggesting this signalling cascade may be responsible for the adverse downstream consequences of these inflammatory cytokines. We suggest a superior approach for treatment of tendinopathy may therefore be to target specific signalling pathways such as NF-κB.

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Section: Introductionmentioning

confidence: 99%

Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell–derived factors

et al. 2022

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“…Amongst these, TNFα (tumour necrosis factor alpha) and IL-1β (interleukin 1 beta) are evidenced to be the most potent inducers of a catabolic response, with recent evidence suggesting these inflammatory cytokines in combination with IFN-γ (interferon gamma) have detrimental consequences for tendon cell function in vitro [13]. Inflammatory cytokines stimulate the activation of specific signalling pathways inside the cell, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription (STATs) [14][15][16]. Our previous work has demonstrated that in adult tenocytes the adverse effects of TNFα and IL-1β are likely caused by their activation of NF-κB [13,17].…”

Section: Introductionmentioning

confidence: 99%

Conservation Challenges: The Limitations of Antemortem Tuberculosis Testing in Captive Asiatic Lions (Panthera Leo Persica)

Molenaar

Burr²,

Swift

et al. 2020

Journal of Zoo and Wildlife Medicine

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Tissue fibrosis following tendon injury is a major clinical problem due to the increased risk of re-injury and limited treatment options; however, its mechanism remains unclear. Evidence suggests that insufficient resolution of inflammation contributes to fibrotic healing by disrupting tenocyte activity, with the NF-κB pathway being identified as a potential mediator. Equine embryonic stem cell (ESC) derived tenocytes may offer a potential cell-based therapy to improve tendon regeneration, but how they respond to an inflammatory environment is largely unknown. Our findings reveal for the first time that, unlike adult tenocytes, ESC-tenocytes are unaffected by IFN-γ, TNFα, and IL-1β stimulation; producing minimal changes to tendon-associated gene expression and generating 3-D collagen gel constructs indistinguishable from unstimulated controls. Inflammatory pathway analysis found these inflammatory cytokines failed to activate NF-κB in the ESC-tenocytes. However, NF-κB could be activated to induce changes in gene expression following stimulation with NF-κB pharmaceutical activators. Transcriptomic analysis revealed differences between cytokine and NF-κB signalling components between adult and ESC-tenocytes, which may contribute to the mechanism by which ESC-tenocytes escape inflammatory stimuli. Further investigation of these molecular mechanisms will help guide novel therapies to reduce fibrosis and encourage superior tendon healing.

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“…GLI2 and GLI3 were also identified as candidate DSLD genes. GLI3 has been linked to mechanotransduction responses during tendon healing ( Freedman et al, 2022 ). In humans, increased expression of MYL1 has been identified in traumatic rotator cuff tears in female patients, whereas MYL2 is highly expressed in degenerative tears in male patients ( Rai et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture and polygenic risk score prediction of degenerative suspensory ligament desmitis (DSLD) in the Peruvian Horse

et al. 2023

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Introduction: Spontaneous rupture of tendons and ligaments is common in several species including humans. In horses, degenerative suspensory ligament desmitis (DSLD) is an important acquired idiopathic disease of a major energy-storing tendon-like structure. DSLD risk is increased in several breeds, including the Peruvian Horse. Affected horses have often been used for breeding before the disease is apparent. Breed predisposition suggests a substantial genetic contribution, but heritability and genetic architecture of DSLD have not been determined.Methods: To identify genomic regions associated with DSLD, we recruited a reference population of 183 Peruvian Horses, phenotyped as DSLD cases or controls, and undertook a genome-wide association study (GWAS), a regional window variance analysis using local genomic partitioning, a signatures of selection (SOS) analysis, and polygenic risk score (PRS) prediction of DSLD risk. We also estimated trait heritability from pedigrees.Results: Heritability was estimated in a population of 1,927 Peruvian horses at 0.22 ± 0.08. After establishing a permutation-based threshold for genome-wide significance, 151 DSLD risk single nucleotide polymorphisms (SNPs) were identified by GWAS. Multiple regions of enriched local heritability were identified across the genome, with strong enrichment signals on chromosomes 1, 2, 6, 10, 13, 16, 18, 22, and the X chromosome. With SOS analysis, there were 66 genes with a selection signature in DSLD cases that was not present in the control group that included the TGFB3 gene. Pathways enriched in DSLD cases included proteoglycan metabolism, extracellular matrix homeostasis, and signal transduction pathways that included the hedgehog signaling pathway. The best PRS predictive performance was obtained when we fitted 1% of top SNPs using a Bayesian Ridge Regression model which achieved the highest mean of R2 on both the probit and logit liability scales, indicating a strong predictive performance.Discussion: We conclude that within-breed GWAS of DSLD in the Peruvian Horse has further confirmed that moderate heritability and a polygenic architecture underlies the trait and identified multiple DSLD SNP associations in novel tendinopathy candidate genes influencing disease risk. Pathways enriched with DSLD risk variants include ones that influence glycosaminoglycan metabolism, extracellular matrix homeostasis, signal transduction pathways.

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Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

Cited by 6 publications

References 51 publications

Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell–derived factors

Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell–derived factors

Conservation Challenges: The Limitations of Antemortem Tuberculosis Testing in Captive Asiatic Lions (Panthera Leo Persica)

Genetic architecture and polygenic risk score prediction of degenerative suspensory ligament desmitis (DSLD) in the Peruvian Horse

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