Spectrum of Tendon Pathologies: Triggers, Trails and End-State

Steinmann, Sara; Pfeifer, Christian; Brochhausen, Christoph; Docheva, Denitsa

doi:10.3390/ijms21030844

Cited by 89 publications

(106 citation statements)

References 97 publications

(152 reference statements)

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“…To increase the knowledge in the MSC field, in the present study we characterized the stability of a wide panel of putative miRNA RGs in hAMSC-EVs to provide a valuable tool in order to fingerprint these microparticles. In particular, the crucial impact of RG choice has been emphasized by highlighting the dramatic differences in the amount of evaluation of few and unrelated tendon-associated miRNAs, chosen as examples due to the emerging role of small RNA gain or loss in tendon homeostasis and tendinopathy development [43][44][45]. In general, the herein-proposed results will be helpful to envision hAMSC-EVs as delivery platforms in the broader context of regenerative-medicine-based approaches, where immunomodulation and regeneration are needed.…”

Section: Introductionmentioning

confidence: 99%

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

et al. 2020

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Human amniotic membrane and amniotic membrane-derived mesenchymal stromal cells (hAMSCs) have produced promising results in regenerative medicine, especially for the treatment of inflammatory-based diseases and for different injuries including those in the orthopedic field such as tendon disorders. hAMSCs have been proposed to exert their anti-inflammatory and healing potential via secreted factors, both free and conveyed within extracellular vesicles (EVs). In particular, EV miRNAs are considered privileged players due to their impact on target cells and tissues, and their future use as therapeutic molecules is being intensely investigated. In this view, EV-miRNA quantification in either research or future clinical products has emerged as a crucial paradigm, although, to date, largely unsolved due to lack of reliable reference genes (RGs). In this study, a panel of thirteen putative miRNA RGs (let-7a-5p, miR-16-5p, miR-22-5p, miR-23a-3p, miR-26a-5p, miR-29a-5p, miR-101-3p, miR-103a-3p, miR-221-3p, miR-423-5p, miR-425-5p, miR-660-5p and U6 snRNA) that were identified in different EV types was assessed in hAMSC-EVs. A validated experimental pipeline was followed, sifting the output of four largely accepted algorithms for RG prediction (geNorm, NormFinder, BestKeeper and ΔCt method). Out of nine RGs constitutively expressed across all EV isolates, miR-101-3p and miR-22-5p resulted in the most stable RGs, whereas miR-423-5p and U6 snRNA performed poorly. miR-22-5p was also previously reported to be a reliable RG in adipose-derived MSC-EVs, suggesting its suitability across samples isolated from different MSC types. Further, to shed light on the impact of incorrect RG choice, the level of five tendon-related miRNAs (miR-29a-3p, miR-135a-5p, miR-146a-5p, miR-337-3p, let-7d-5p) was compared among hAMSC-EVs isolates. The use of miR-423-5p and U6 snRNA did not allow a correct quantification of miRNA incorporation in EVs, leading to less accurate fingerprinting and, if used for potency prediction, misleading indication of the most appropriate clinical batch. These results emphasize the crucial importance of RG choice for EV-miRNAs in hAMSCs studies and contribute to the identification of reliable RGs such as miR-101-3p and miR-22-5p to be validated in other MSC-EVs related fields.

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Section: Introductionmentioning

confidence: 99%

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

et al. 2020

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“…By 4 months-of-age, Crtap -/- Achilles tendons and patellar ligaments remained thinner and hypercellular compared to wildtype and heterozygous mice (Figure 1G-L); in addition, synovial hyperplasia persisted within Crtap -/- knees (Figure 1L). Interestingly, ectopic chondrogenesis was present towards either end of the patellar ligament and/or cruciate ligaments in some (but not all) 4-month-old Crtap -/- mice (Figure 1L) – a phenomenon that can occur in tendinopathy 27 .…”

Section: Resultsmentioning

confidence: 99%

Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta

Grol

Haelterman

Munivez

et al. 2020

Preprint

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24Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue disorders 25 characterized by variable short stature, skeletal deformities, low bone mass with increased bone 26 fragility, and motor deficits. The majority of cases are caused by mutations in type I collagen, or 27 by mutations that affect collagen processing and/or modification. Like bone, the extracellular 28 matrix of tendons and ligaments is largely made up of type I collagen; however, despite the fact 29 that a subset of OI patients presents with joint hypermobility, how tendon/ligament dysfunction 30 contributes to this is unknown. Here, we performed a detailed phenotypic characterization of the 31 flexor digitorum longus (FDL) tendon, Achilles tendon and patellar ligament in the Crtap mutant 32 mouse model of severe, recessive OI. Stable, pyridinoline collagen cross-links were increased by 33 5-to 10-fold in mutant tendons and ligaments. Collagen fibril size in all three structures was also 34 smaller in Crtap -/mice compared to wildtype or heterozygous littermates. Together, these 35 ultrastructural and biochemical changes resulted in thinner tendons and ligaments with increased 36 cellularity compared to controls, as assessed by histology. To examine how alterations in tendons 37 might affect motor function, we performed a battery of behavioral assays. During open field 38 assessment, Crtap -/mice exhibited reduced horizontal and vertical activity. Crtap -/mice also 39 exhibited motor impairments on the rotarod and grid footslip tests. In addition, Crtap -/mice had 40 reduced grip strength and displayed reduced time on the inverted grid test, indicating that they 41 are weaker than wildtype and heterozygous mice. In summary, these data demonstrate that the 42 tendons/ligaments of Crtap -/mice are pathologically altered compared to wildtype -a 43 phenotype that correlates with motor deficits and grip strength impairments. As such, Crtap -/-44 mice provide a preclinical model with which to examine downstream mechanisms and therapies 45 pertaining to tendon/ligament pathology and motor dysfunction for OI patients. 46 48 ligaments connect articulating bones to support joint alignment and function 1, 2 . The extracellular 49 matrix of tendons and ligaments is primarily composed of type I collagen as well as smaller 50 quantities of other collagens and proteoglycans 3 . During development, the collagen fibrils in 51 tendons and ligaments develop through addition and lengthening before transitioning to 52 appositional fusion of existing fibers with continued lengthening in post-natal life 4 . The synthesis 53 and assembly of this collagen-rich matrix is influenced by other small collagens and 54 proteoglycans as well as by the cross-linking chemistry of type I procollagen fibrils, which in 55 turn regulates fibril size and strength 5 . Like tendon and ligament, the organic matrix of bone 56 consists largely of type I collagen 6 , and disruptions in collagen synthesis and folding have been 57 shown to negatively impact its biochemical ...

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“…This Special Issue aimed to embrace research and review articles concentrating on: The spectrum of tendon pathologies: e.g., triggers, trails, and end-state of tendinopathy by Steinmann et al [ 1 ]. Endogenous tendon cells and their governing molecular pathways: e.g., cell–extracellular matrix (ECM) contacts mediated via α2β1 integrin by Kronenberg et al [ 2 ]; transforming growth factor beta-activated kinase-1 (TAK 1) signaling in tendon and enthesis by Friese et al [ 3 ]; and transcriptional activity of the early growth response 1 ( EGR1 ) gene in healthy and scarred tendons by Havis et al [ 4 ].…”

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confidence: 99%

“… Tendon structural composition and biomechanical properties: e.g., alterations in elastic properties after tendon injury by Frankewycz et al [ 10 ] and in vitro and in vivo response of tenocytes to mechanical stimulation by Fleischhacker et al [ 11 ]. Medicinal and tissue engineering therapeutic approaches: e.g., pulsed electromagnetic field (PEMF)-based therapy by Vinhas et al [ 5 ]; various percutaneous treatments by Darrieutort-Laffite et al [ 12 ]; enthesial regenerative approaches by Friese et al [ 3 ]; and current tendinopathy management strategies by Steinmann et al [ 1 ]. …”

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confidence: 99%

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Editorial for Special Issue: Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches

Docheva

2020

IJMS

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Spectrum of Tendon Pathologies: Triggers, Trails and End-State

Cited by 89 publications

References 97 publications

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta

Editorial for Special Issue: Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches

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Spectrum of Tendon Pathologies: Triggers, Trails and End-State

Cited by 89 publications

References 97 publications

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

miRNA Reference Genes in Extracellular Vesicles Released from Amniotic Membrane-Derived Mesenchymal Stromal Cells

Tendon and Motor Phenotypes in theCrtap-/-Mouse Model of Recessive Osteogenesis Imperfecta

Editorial for Special Issue: Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches

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Tendon and Motor Phenotypes in theCrtap^-/-Mouse Model of Recessive Osteogenesis Imperfecta