Musculoskeletal System - Tendon Development

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Introduction

Myotendinous junction
Myotendinous junction

This page describes skeletal tendon development, during formation of the connective tissue connection muscle to bone.

The syndetome is the embryonic structural origin of tendons from the somite and originates from the dorsolateral edge of the sclerotome. Expression of the basic helix-loop-helix (bHLH) transcription factor scleraxis (SCX) in early progenitor cells is thought to be key regulator in the formation of tendon and ligament tissues.[1] Scleraxis may also have additional roles in other tissues such as in early heart valve development.[2]

The origins of some muscles and tendons in the head differ from those found in the remained of the body.


See also notes Connective Tissue Development.


Musculoskeletal Links: Introduction | mesoderm | somitogenesis | limb | cartilage | bone | bone timeline | shoulder | pelvis | axial skeleton | skull | joint | skeletal muscle | muscle timeline | tendon | diaphragm | Lecture - Musculoskeletal | Lecture Movie | musculoskeletal abnormalities | limb abnormalities | developmental hip dysplasia | cartilage histology | bone histology | Skeletal Muscle Histology | Category:Musculoskeletal
Historic Musculoskeletal Embryology  
1853 Bone | 1885 Sphenoid | 1902 - Pubo-femoral Region | Spinal Column and Back | Body Segmentation | Cranium | Body Wall, Ribs, and Sternum | Limbs | 1901 - Limbs | 1902 - Arm Development | 1906 Human Embryo Ossification | 1906 Lower limb Nerves and Muscle | 1907 - Muscular System | Skeleton and Limbs | 1908 Vertebra | 1908 Cervical Vertebra | 1909 Mandible | 1910 - Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | 1913 Clavicle | 1920 Clavicle | 1921 - External body form | Connective tissues and skeletal | Muscular | Diaphragm | 1929 Rat Somite | 1932 Pelvis | 1940 Synovial Joints | 1943 Human Embryonic, Fetal and Circumnatal Skeleton | 1947 Joints | 1949 Cartilage and Bone | 1957 Chondrification Hands and Feet | 1968 Knee

Some Recent Findings

  • mTORC1 Signaling is a Critical Regulator of Postnatal Tendon Development[3] "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."
  • Cellular and molecular maturation in fetal and adult ovine calcaneal tendons[4] "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."
  • Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin.[5] "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.... 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."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Tendon development

Phong K Nguyen, Xuan Sabrina Pan, Jiewen Li, Catherine K Kuo Roadmap of molecular, compositional, and functional markers during embryonic tendon development. Connect. Tissue Res.: 2018;1-14 PubMed 30231651

Chi-Fen Hsieh, Zexing Yan, Ricarda G Schumann, Stefan Milz, Christian G Pfeifer, Matthias Schieker, Denitsa Docheva In Vitro Comparison of 2D-Cell Culture and 3D-Cell Sheets of Scleraxis-Programmed Bone Marrow Derived Mesenchymal Stem Cells to Primary Tendon Stem/Progenitor Cells for Tendon Repair. Int J Mol Sci: 2018, 19(8); PubMed 30072668

Sabine Conrad, Kathrin Weber, Ulrich Walliser, Florian Geburek, Thomas Skutella Stem Cell Therapy for Tendon Regeneration: Current Status and Future Directions. Adv. Exp. Med. Biol.: 2018; PubMed 30043235

Manuel Delgado Caceres, Christian Pfeifer, Denitsa Docheva Understanding tendons: lessons from transgenic mouse models. Stem Cells Dev.: 2018; PubMed 29978741

Jeremy A Dubin, Daniel R Greenberg, Kag C Iglinski-Benjamin, Geoffrey D Abrams Effect of Micro-RNA on Tenocytes and Tendon-Related Gene Expression: A Systematic Review. J. Orthop. Res.: 2018; PubMed 29873411


Search term: syndetome Taiki Nakajima, Mitsuaki Shibata, Megumi Nishio, Sanae Nagata, Cantas Alev, Hidetoshi Sakurai, Junya Toguchida, Makoto Ikeya Modeling human somite development and fibrodysplasia ossificans progressiva with induced pluripotent stem cells. Development: 2018, 145(16); PubMed 30139810

Guang Yang, Benjamin B Rothrauff, Rocky S Tuan Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res. C Embryo Today: 2013, 99(3);203-22 PubMed 24078497

Yuki Sugimoto, Aki Takimoto, Yuji Hiraki, Chisa Shukunami Generation and characterization of ScxCre transgenic mice. Genesis: 2013, 51(4);275-83 PubMed 23349075

Paolo Alberton, Cvetan Popov, Markus Prägert, Julia Kohler, Chisa Shukunami, Matthias Schieker, Denitsa Docheva Conversion of human bone marrow-derived mesenchymal stem cells into tendon progenitor cells by ectopic expression of scleraxis. Stem Cells Dev.: 2012, 21(6);846-58 PubMed 21988170

Venugopal Rao Mittapalli, Bodo Christ, Felicitas Pröls, Martin Scaal Pleiotrophin is expressed in avian somites and tendon anlagen. Histochem. Cell Biol.: 2009, 132(4);413-22 PubMed 19526365


Older papers  
  • Connecting muscles to tendons: tendons and musculoskeletal development in flies and vertebrates[6] "The formation of the musculoskeletal system represents an intricate process of tissue assembly involving heterotypic inductive interactions between tendons, muscles and cartilage. An essential component of all musculoskeletal systems is the anchoring of the force-generating muscles to the solid support of the organism: the skeleton in vertebrates and the exoskeleton in invertebrates. Here, we discuss recent findings that illuminate musculoskeletal assembly in the vertebrate embryo, findings that emphasize the reciprocal interactions between the forming tendons, muscle and cartilage tissues. We also compare these events with those of the corresponding system in the Drosophila embryo, highlighting distinct and common pathways that promote efficient locomotion while preserving the form of the organism."
  • Slowdown promotes muscle integrity by modulating integrin-mediated adhesion at the myotendinous junction[7]

Molecular

Mesoderm Development and Pax cartoon

Mesoderm Development and Pax[8]

dark green - syndetome originates from the dorsolateral edge of the sclerotome, as Pax1 and Pax9 are downregulated and scleraxis (Scx) upregulation leads to syndegenesis. Pax, paired homeobox; MYOD1, myogenic differentiation antigen 1; MYF5, myogenic factor 5; NKX, NK homeobox; SCX, scleraxis.

Scleraxis

Scleraxis (SCX) is a member of the basic helix-loop-helix (bHLH) transcription factor family. It is expressed in early mesoderm progenitor cells and may regulate the formation of tendon and ligament tissues.[1]

Scleraxis may also have additional roles in other tissues such as in early heart valve development.[2]

  • Cytogenetic location: 8q24.3


Links: NCBI databases - Scleraxis | OMIM 609067

Tenomodulin

Tenomodulin (TNMD, Tnmd) is a marker of tendon differentiation, its expression has been shown to be regulated by the transcription factors Scleraxis and Mohawk.[9] May also affect the tendon stem/progenitor cells.


Links: NCBI databases - Tenomodulin

Histology

References

  1. 1.0 1.1 R Schweitzer, J H Chyung, L C Murtaugh, A E Brent, V Rosen, E N Olson, A Lassar, C J Tabin Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development: 2001, 128(19);3855-66 PubMed 11585810 Cite error: Invalid <ref> tag; name "PMID11585810" defined multiple times with different content
  2. 2.0 2.1 Barnette DN, VandeKopple M, Wu Y, Willoughby DA & Lincoln J. (2014). RNA-seq analysis to identify novel roles of scleraxis during embryonic mouse heart valve remodeling. PLoS ONE , 9, e101425. PMID: 24983472 DOI.
  3. Lim J, Munivez E, Jiang MM, Song IW, Gannon F, Keene DR, Schweitzer R, Lee BH & Joeng KS. (2017). mTORC1 Signaling is a Critical Regulator of Postnatal Tendon Development. Sci Rep , 7, 17175. PMID: 29215029 DOI.
  4. Russo V, Mauro A, Martelli A, Di Giacinto O, Di Marcantonio L, Nardinocchi D, Berardinelli P & Barboni B. (2015). Cellular and molecular maturation in fetal and adult ovine calcaneal tendons. J. Anat. , 226, 126-42. PMID: 25546075 DOI.
  5. Brown JP, Finley VG & Kuo CK. (2014). Embryonic mechanical and soluble cues regulate tendon progenitor cell gene expression as a function of developmental stage and anatomical origin. J Biomech , 47, 214-22. PMID: 24231248 DOI.
  6. Schweitzer R, Zelzer E & Volk T. (2010). Connecting muscles to tendons: tendons and musculoskeletal development in flies and vertebrates. Development , 137, 2807-17. PMID: 20699295 DOI.
  7. Gilsohn E & Volk T. (2010). Slowdown promotes muscle integrity by modulating integrin-mediated adhesion at the myotendinous junction. Development , 137, 785-94. PMID: 20110313 DOI.
  8. Blake JA & Ziman MR. (2014). Pax genes: regulators of lineage specification and progenitor cell maintenance. Development , 141, 737-51. PMID: 24496612 DOI.
  9. Miyabara S, Yuda Y, Kasashima Y, Kuwano A & Arai K. (2014). Regulation of Tenomodulin Expression Via Wnt/β-catenin Signaling in Equine Bone Marrow-derived Mesenchymal Stem Cells. J Equine Sci , 25, 7-13. PMID: 24834008 DOI.

Reviews

Articles

Brent AE, Schweitzer R & Tabin CJ. (2003). A somitic compartment of tendon progenitors. Cell , 113, 235-48. PMID: 12705871

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Cite this page: Hill, M.A. (2018, December 10) Embryology Musculoskeletal System - Tendon Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Musculoskeletal_System_-_Tendon_Development

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© Dr Mark Hill 2018, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G