Talk:Musculoskeletal System - Tendon Development

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Cite this page: Hill, M.A. (2019, September 18) Embryology Musculoskeletal System - Tendon Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Musculoskeletal_System_-_Tendon_Development

10 Most Recent Papers

Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)


Tendon Embryology

<pubmed limit=5>Tendon Embryology</pubmed>

Tendon Development

<pubmed limit=5>Tendon Development</pubmed>

2017

mTORC1 Signaling is a Critical Regulator of Postnatal Tendon Development

Sci Rep. 2017 Dec 7;7(1):17175. doi: 10.1038/s41598-017-17384-0.

Lim J1, Munivez E1, Jiang MM1, Song IW1, Gannon F2, Keene DR3, Schweitzer R3, Lee BH4, Joeng KS1.

Abstract

Tendons transmit contractile forces between musculoskeletal tissues. Whereas the biomechanical properties of tendons have been studied extensively, the molecular mechanisms regulating postnatal tendon development are not well understood. Here we examine the role of mTORC1 signaling in postnatal tendon development using mouse genetic approaches. Loss of mTORC1 signaling by removal of Raptor in tendons caused severe tendon defects postnatally, including decreased tendon thickness, indicating that mTORC1 is necessary for postnatal tendon development. By contrast, activation of mTORC1 signaling in tendons increased tendon cell numbers and proliferation. In addition, Tsc1 conditional knockout mice presented severely disorganized collagen fibers and neovascularization in the tendon midsubstance. Interestingly, collagen fibril diameter was significantly reduced in both Raptor and Tsc1 conditional knockout mice, albeit with variations in severity. We performed RNA-seq analysis using Achilles tendons to investigate the molecular changes underlying these tendon phenotypes. Raptor conditional knockout mice showed decreased extracellular matrix (ECM) structure-related gene expression, whereas Tsc1 conditional knockout mice exhibited changes in genes regulating TGF-β/BMP/FGF signaling, as well as in genes controlling ECM structure and disassembly. Collectively, our studies suggest that maintaining physiological levels of mTORC1 signaling is essential for postnatal tendon development and maturation. PMID: 29215029 PMCID: PMC5719403 DOI: 10.1038/s41598-017-17384-0

Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load

EBioMedicine. 2017 Jun;20:240-254. doi: 10.1016/j.ebiom.2017.05.003. Epub 2017 May 5.

Dex S1, Alberton P1, Willkomm L2, Söllradl T3, Bago S3, Milz S4, Shakibaei M4, Ignatius A5, Bloch W2, Clausen-Schaumann H3, Shukunami C6, Schieker M7, Docheva D8.

Abstract

Tendons are dense connective tissues that attach muscles to bone with an indispensable role in locomotion because of their intrinsic properties of storing and releasing muscle- generated elastic energy. Tenomodulin (Tnmd) is a well-accepted gene marker for the mature tendon/ligament lineage and its loss-of -function in mice leads to a phenotype with distinct signs of premature aging on tissue and stem/progenitor cell levels. Based on these findings, we hypothesized that Tnmd might be an important factor in the functional performance of tendons. Firstly, we revealed that Tnmd is a mechanosensitive gene and that the C-terminus of the protein co-localize with collagen I-type fibers in the extracellular matrix. Secondly, using an endurance training protocol, we compared Tnmd knockout mice with wild types and showed that Tnmd deficiency leads to significantly inferior running performance that further worsens with training. In these mice, endurance running was hindered due to abnormal response of collagen I cross-linking and proteoglycan genes leading to an inadequate collagen I fiber thickness and elasticity. In sum, our study demonstrates that Tnmd is required for proper tendon tissue adaptation to endurance running and aids in better understanding of the structural-functional relationships of tendon tissues. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Atomic force microscopy; Collagen I crosslinking; Knockout mouse model; Running tests; Tendons; Tenomodulin PMID: 28566251 PMCID: PMC5478207 DOI: 10.1016/j.ebiom.2017.05.003

2016

Tenogenic modulating insider factor: Systematic assessment on the functions of tenomodulin gene

Gene. 2016 Aug 1;587(1):1-17. doi: 10.1016/j.gene.2016.04.051. Epub 2016 Apr 26.

Dex S1, Lin D1, Shukunami C2, Docheva D3.

Abstract

Tenomodulin (TNMD, Tnmd) is a gene highly expressed in tendon known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. This review aims at providing an encompassing overview of this gene and its protein. In addition, its known expression pattern as well as putative signalling pathways will be described. A chronological overview of the discovered functions of this gene in tendon and other tissues and cells is provided as well as its use as a tendon and ligament lineage marker is assessed in detail and discussed. Last, information about the possible connections between TNMD genomic mutations and mRNA expression to various diseases is delivered. Taken together this review offers a solid synopsis on the up-to-date information available about TNMD and aids at directing and focusing the future research to fully uncover the roles and implications of this interesting gene. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

KEYWORDS: BRICHOS; Cell differentiation; Chordae tendineae cordis; Eye; Gene marker; Knockout mice; Metabolic syndrome; Obesity; Periodontal ligament; Single nucleotide polymorphism; Tendon; Tendon stem/progenitor cells; Tenomodulin; Vasculature

PMID: 27129941 PMCID: PMC4897592 DOI: 10.1016/j.gene.2016.04.051

2014

Cellular and molecular maturation in fetal and adult ovine calcaneal tendons

J Anat. 2014 Dec 25. doi: 10.1111/joa.12269. [Epub ahead of print]

Russo V1, Mauro A, Martelli A, Di Giacinto O, Di Marcantonio L, Nardinocchi D, Berardinelli P, Barboni B.

Abstract

Processes of development during fetal life profoundly transform tendons from a plastic tissue into a highly differentiated structure, characterised by a very low ability to regenerate after injury in adulthood. Sheep tendon is frequently used as a translational model to investigate cell-based regenerative approaches. However, in contrast to other species, analytical and comparative baseline studies on the normal developmental maturation of sheep tendons from fetal through to adult life are not currently available. Thus, a detailed morphological and biochemical study was designed to characterise tissue maturation during mid- (2 months of pregnancy: 14 cm of length) and late fetal (4 months: 40 cm of length) life, through to adulthood. The results confirm that ovine tendon morphology undergoes profound transformations during this period. Endotenon was more developed in fetal tendons than in adult tissues, and its cell phenotype changed through tendon maturation. Indeed, groups of large rounded cells laying on smaller and more compacted ones expressing osteocalcin, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were identified exclusively in fetal mid-stage tissues, and not in late fetal or adult tendons. VEGF, NGF as well as blood vessels and nerve fibers showed decreased expression during tendon development. Moreover, the endotenon of mid- and late fetuses contained identifiable cells that expressed several pluripotent stem cell markers [Telomerase Reverse Transcriptase (TERT), SRY Determining Region Y Box-2 (SOX2), Nanog Homeobox (NANOG) and Octamer Binding Transcription Factor-4A (OCT-4A)]. These cells were not identifiable in adult specimens. Ovine tendon development was also accompanied by morphological modifications to cell nuclei, and a progressive decrease in cellularity, proliferation index and expression of connexins 43 and 32. Tendon maturation was similarly characterised by modulation of several other gene expression profiles, including Collagen type I, Collagen type III, Scleraxis B, Tenomodulin, Trombospondin 4 and Osteocalcin. These gene profiles underwent a dramatic reduction in adult tissues. Transforming growth factor-β~1 expression (involved in collagen synthesis) underwent a similar decrease. In conclusion, these morphological studies carried out on sheep tendons at different stages of development and aging offer normal structural and molecular baseline data to allow accurate evaluation of data from subsequent interventional studies investigating tendon healing and regeneration in ovine experimental models. © 2014 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society. KEYWORDS: blood vessels; calcaneal tendon; connexins; extracellular matrix molecules; fetus; growth factors; nerve fibers; pluripotency stem cell markers PMID 25546075


Regulation of Tenomodulin Expression Via Wnt/β-catenin Signaling in Equine Bone Marrow-derived Mesenchymal Stem Cells

J Equine Sci. 2014;25(1):7-13. doi: 10.1294/jes.25.7. Epub 2014 Apr 22.

Miyabara S1, Yuda Y1, Kasashima Y2, Kuwano A2, Arai K1.

Abstract

Tenomodulin has been recognized as a biomarker for tendon differentiation, and its gene expression is regulated by several transcription factors including Scleraxis and Mohawk. In this study, we found a novel regulatory mechanism of tenomodulin expression. Equine bone marrow-derived mesenchymal stem cells (BMSCs) in monolayer culture showed a low mRNA level of tenomodulin in comparison with the level in the tendon. When cultured in collagen gel containing a glycogen synthase kinase-3 (GSK-3) inhibitor (BIO), expression of tenomodulin in BMSCs increased up to the level in the tendon. Participation of GSK-3 in its gene expression was further demonstrated by a gene silencing experiment with small interference RNA corresponding to GSK-3, suggesting that Wnt/β-catenin signaling mediated expression of tenomodulin. These results were confirmed by nuclear translocation of β-catenin in BIO-treated BMSCs cultured in collagen gel. Under this culture condition, expression of tenomodulin-related transcription factors including Scleraxis and Mohawk was not affected, suggesting that Wnt/β-catenin signaling was independent from these transcription factors. Additionally, BIO strongly enhanced expression of type XIV collagen in collagen-embedded BMSCs up to the level in the tendon, and other tendon-related extracellular matrix components such as decorin and fibromodulin were also upregulated. Taken together, these results indicated that activation of Wnt/β-catenin signaling could induce differentiation of BMSCs into tenomodulin-expressing tendon cells in collagen gel. KEYWORDS: BMSCs; ECM; Wnt signaling; tendon; tenomodulin

PMID 24834008

Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin

J Biomech. 2014 Jan 3;47(1):214-22. doi: 10.1016/j.jbiomech.2013.09.018. Epub 2013 Oct 30.

Brown JP1, Finley VG1, Kuo CK2. Author information

Abstract

Stem cell-based engineering strategies for tendons have yet to yield a normal functional tissue, due in part to a need for tenogenic factors. Additionally, the ability to evaluate differentiation has been challenged by a lack of markers for differentiation. We propose to inform tendon regeneration with developmental cues involved in normal tissue formation and with phenotypic markers that are characteristic of differentiating tendon progenitor cells (TPCs). Mechanical forces, fibroblast growth factor (FGF)-4 and transforming growth factor (TGF)-β2 are implicated in embryonic tendon development, yet the isolated effects of these factors on differentiating TPCs are unknown. Additionally, developmental mechanisms vary between limb and axial tendons, suggesting the respective cell types are programmed to respond uniquely to exogenous factors. To characterize developmental cues and benchmarks for differentiation toward limb vs. axial phenotypes, we dynamically loaded and treated TPCs with growth factors and assessed gene expression profiles as a function of developmental stage and anatomical origin. Based on scleraxis expression, TGFβ2 was tenogenic for TPCs at all stages, while loading was for late-stage cells only, and FGF4 had no effect despite regulation of other genes. When factors were combined, TGFβ2 continued to be tenogenic, while FGF4 appeared anti-tenogenic. Various treatments elicited distinct responses by axial vs. limb TPCs of specific stages. These results identified tenogenic factors, suggest tendon engineering strategies should be customized for tissues by anatomical origin, and provide stage-specific gene expression profiles of limb and axial TPCs as benchmarks with which to monitor tenogenic differentiation of stem cells. © 2013 Elsevier Ltd. All rights reserved. KEYWORDS: Development, Differentiation, Embryonic, Growth factor, Mechanical loading, Tendon

PMID 24231248

Morphogenesis of rat myotendinous junction

Muscles Ligaments Tendons J. 2014 Feb 24;3(4):275-80. eCollection 2013.

Curzi D, Ambrogini P, Falcieri E, Burattini S. Author information

Abstract Myotendinous junction (MTJ) is the highly specialized complex which connects the skeletal muscle to the tendon for transmitting the contractile force between the two tissues. The purpose of this study was to investigate the MTJ development and rat EDL was chosen as a model. 1, 15, 30 day animals were considered and the junctions were analyzed by light and electron microscopy. The MTJ interface architecture increased during the development, extending the interaction between muscle and tendon. 1-day-old rats showed disorganized myofibril bundles, spread cytosol and incomplete rough endoplasmic reticulum, features partially improved in 15-day-old rats, and completely developed in 30-day-old animals. These findings indicate that muscle-tendon interface displays, during rat lifetime, numerically increased and longer tendon interdigitations, correlated with an improved organization of both tissues and with a progressive acquirement of full functionality. KEYWORDS: morphogenesis, myotendinous junction, skeletal muscle, ultrastructure

PMID 24596690

2013

Cell. 2003 Apr 18;113(2):235-48. A somitic compartment of tendon progenitors.

Brent AE1, Schweitzer R, Tabin CJ. Author information Abstract We demonstrate that the tendons associated with the axial skeleton derive from a heretofore unappreciated, fourth compartment of the somites. Scleraxis (Scx), a bHLH transcription factor, marks this somitic tendon progenitor population at its inception, and is continuously expressed through differentiation into the mature tendons. Two earlier-formed somitic compartments, the sclerotome and myotome, interact to establish this fourth Scx-positive compartment. The tendon progenitors are induced at the sclerotome's edge, at the expense of skeletogenic Pax1 positive cells and in response to FGF signaling in the adjacent myotome. The tendon primordia thus form in a location abutting the two tissues that the mature tendons must ultimately connect. Tendon progenitor formation may reveal a general mechanism for the specification of other somitic subcompartments. Comment in Welcome to syndetome: a new somitic compartment. [Dev Cell. 2003] PMID: 12705871

2009

Relationship between neural crest cells and cranial mesoderm during head muscle development

PLoS One. 2009;4(2):e4381. Epub 2009 Feb 9.


Grenier J, Teillet MA, Grifone R, Kelly RG, Duprez D. Source CNRS, UMR 7622 Biologie Moléculaire et Cellulaire du Développement, Université Pierre et Marie Curie, Paris, France.

Abstract

BACKGROUND: In vertebrates, the skeletal elements of the jaw, together with the connective tissues and tendons, originate from neural crest cells, while the associated muscles derive mainly from cranial mesoderm. Previous studies have shown that neural crest cells migrate in close association with cranial mesoderm and then circumscribe but do not penetrate the core of muscle precursor cells of the branchial arches at early stages of development, thus defining a sharp boundary between neural crest cells and mesodermal muscle progenitor cells. Tendons constitute one of the neural crest derivatives likely to interact with muscle formation. However, head tendon formation has not been studied, nor have tendon and muscle interactions in the head. METHODOLOGY/PRINCIPAL FINDINGS: Reinvestigation of the relationship between cranial neural crest cells and muscle precursor cells during development of the first branchial arch, using quail/chick chimeras and molecular markers revealed several novel features concerning the interface between neural crest cells and mesoderm. We observed that neural crest cells migrate into the cephalic mesoderm containing myogenic precursor cells, leading to the presence of neural crest cells inside the mesodermal core of the first branchial arch. We have also established that all the forming tendons associated with branchiomeric and eye muscles are of neural crest origin and express the Scleraxis marker in chick and mouse embryos. Moreover, analysis of Scleraxis expression in the absence of branchiomeric muscles in Tbx1(-/-) mutant mice, showed that muscles are not necessary for the initiation of tendon formation but are required for further tendon development. CONCLUSIONS/SIGNIFICANCE: This results show that neural crest cells and muscle progenitor cells are more extensively mixed than previously believed during arch development. In addition, our results show that interactions between muscles and tendons during craniofacial development are similar to those observed in the limb, despite the distinct embryological origin of these cell types in the head.

PMID 19198652

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004381

2005

Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development

Development. 2005 Feb;132(3):515-28. Epub 2005 Jan 5.

Brent AE, Braun T, Tabin CJ. Source Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Abstract

Proper formation of the musculoskeletal system requires the coordinated development of the muscle, cartilage and tendon lineages arising from the somitic mesoderm. During early somite development, muscle and cartilage emerge from two distinct compartments, the myotome and sclerotome, in response to signals secreted from surrounding tissues. As the somite matures, the tendon lineage is established within the dorsolateral sclerotome, adjacent to and beneath the myotome. We examine interactions between the three lineages by observing tendon development in mouse mutants with genetically disrupted muscle or cartilage development. Through analysis of embryos carrying null mutations in Myf5 and Myod1, hence lacking both muscle progenitors and differentiated muscle, we identify an essential role for the specified myotome in axial tendon development, and suggest that absence of tendon formation in Myf5/Myod1 mutants results from loss of the myotomal FGF proteins, which depend upon Myf5 and Myod1 for their expression, and are required, in turn, for induction of the tendon progenitor markers. Our analysis of Sox5/Sox6 double mutants, in which the chondroprogenitors are unable to differentiate into cartilage, reveals that the two cell fates arising from the sclerotome, axial tendon and cartilage are alternative lineages, and that cartilage differentiation is required to actively repress tendon development in the dorsolateral sclerotome.

PMID 15634692

Tendon Development

Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development

Development. 2005 Feb;132(3):515-28. Epub 2005 Jan 5.

Brent AE, Braun T, Tabin CJ. Source Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Abstract

Proper formation of the musculoskeletal system requires the coordinated development of the muscle, cartilage and tendon lineages arising from the somitic mesoderm. During early somite development, muscle and cartilage emerge from two distinct compartments, the myotome and sclerotome, in response to signals secreted from surrounding tissues. As the somite matures, the tendon lineage is established within the dorsolateral sclerotome, adjacent to and beneath the myotome. We examine interactions between the three lineages by observing tendon development in mouse mutants with genetically disrupted muscle or cartilage development. Through analysis of embryos carrying null mutations in Myf5 and Myod1, hence lacking both muscle progenitors and differentiated muscle, we identify an essential role for the specified myotome in axial tendon development, and suggest that absence of tendon formation in Myf5/Myod1 mutants results from loss of the myotomal FGF proteins, which depend upon Myf5 and Myod1 for their expression, and are required, in turn, for induction of the tendon progenitor markers. Our analysis of Sox5/Sox6 double mutants, in which the chondroprogenitors are unable to differentiate into cartilage, reveals that the two cell fates arising from the sclerotome, axial tendon and cartilage are alternative lineages, and that cartilage differentiation is required to actively repress tendon development in the dorsolateral sclerotome.

PMID: 15634692 http://www.ncbi.nlm.nih.gov/pubmed/15634692

2003

A somitic compartment of tendon progenitors

Cell. 2003 Apr 18;113(2):235-48.

Brent AE1, Schweitzer R, Tabin CJ.

Abstract

We demonstrate that the tendons associated with the axial skeleton derive from a heretofore unappreciated, fourth compartment of the somites. Scleraxis (Scx), a bHLH transcription factor, marks this somitic tendon progenitor population at its inception, and is continuously expressed through differentiation into the mature tendons. Two earlier-formed somitic compartments, the sclerotome and myotome, interact to establish this fourth Scx-positive compartment. The tendon progenitors are induced at the sclerotome's edge, at the expense of skeletogenic Pax1 positive cells and in response to FGF signaling in the adjacent myotome. The tendon primordia thus form in a location abutting the two tissues that the mature tendons must ultimately connect. Tendon progenitor formation may reveal a general mechanism for the specification of other somitic subcompartments. Comment in Welcome to syndetome: a new somitic compartment. [Dev Cell. 2003] PMID: 12705871

Welcome to syndetome: a new somitic compartment

Dev Cell. 2003 May;4(5):611-2.

Dubrulle J, Pourquie O. Source Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. Abstract Virtually nothing was known about the embryonic origin of tendons, until a recent paper by Brent and colleagues in which they track the origin of tendon progenitors of the body axis and reveal the molecular events and tissue interactions leading to their commitment.

Comment on Cell. 2003 Apr 18;113(2):235-48. PMID: 12737797


A somitic compartment of tendon progenitors

Cell. 2003 Apr 18;113(2):235-48.

Brent AE, Schweitzer R, Tabin CJ. Source Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Abstract

We demonstrate that the tendons associated with the axial skeleton derive from a heretofore unappreciated, fourth compartment of the somites. Scleraxis (Scx), a bHLH transcription factor, marks this somitic tendon progenitor population at its inception, and is continuously expressed through differentiation into the mature tendons. Two earlier-formed somitic compartments, the sclerotome and myotome, interact to establish this fourth Scx-positive compartment. The tendon progenitors are induced at the sclerotome's edge, at the expense of skeletogenic Pax1 positive cells and in response to FGF signaling in the adjacent myotome. The tendon primordia thus form in a location abutting the two tissues that the mature tendons must ultimately connect. Tendon progenitor formation may reveal a general mechanism for the specification of other somitic subcompartments.

Comment in Dev Cell. 2003 May;4(5):611-2.

PMID 12705871