Menu

Close

Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

Dirk Hubmacher, Stetson Thacker, Sheila M Adams, David Birk, Ronen Schweitzer, Suneel Apte

Preprint posted on April 24, 2018 https://www.biorxiv.org/content/early/2018/04/24/307496

The long and the short of limb growth: impairment of soft-tissue architecture via Adamtsl2 deletion reduces long-bone growth, adding evidence of a coupling mechanism that ensures that all tissues grow in coordination within the vertebrate limb

Selected by Alberto Rosello-Diez

Background

Most organs are composed of different tissues that follow an intrinsic developmental program based on their set of expressed genes. However, the internal architecture of organs is preserved as they grow, suggesting that there is communication between tissues within organs, so that they grow in coordination. The molecular mechanisms for this inter-tissue communication remain quite elusive, aside from a few exceptions regarding limb growth. Two studies (one of them by yours truly et al.) showed that joint tissues communicate with the growth plate (the region driving long bone growth), and that signalling imbalance in the joint can impact on bone growth [1,2]. The current preprint sheds more light on this obscure topic. While modelling human musculoskeletal diseases due to changes in microfibril structure, Hubmacher and colleagues unexpectedly found new evidence of the coupling between growth of bones and the soft tissues in mouse limbs. They were studying the function of Adamtsl2, which encodes a secreted glycoprotein involved in fibril structure.

Key findings

Hubmacher et al. deleted the gene Adamtsl2 in several tissues of the limb, and analysed the effect on limb growth and soft-tissue architecture. They made several significant findings:

  1. During late gestation, Adamtsl2 is expressed in the developing tendons, the outer prospective articular cartilage and the skeletal muscle. Postnatally, it gets restricted to tendons, a thin layer of skin, muscle spindles and the superficial meniscus. In other words it is never expressed in the developing bones.
  2. Conditional deletion of Adamtsl2 in the limb mesenchyme using Prx1-Cre [3] leads to some expected effects, such as altered architecture and composition of microfibrils (e.g. an embryonic code of fibrillin is retained).
  3. Unexpectedly, the mutant animals display reduced bone growth postnatally, especially in the hindlimbs, although not at birth. The bones are also stubbier, with a wider shaft. Importantly, the authors could not find defects in the height of the growth plate, although other parameters were not analysed.
  4. The authors noticed that the Achilles tendon was shorter in the mutant limbs, which prompted them to delete Adamtsl2 exclusively in the tendons, using Scx-Cre. Intriguingly, the bones were also shorter in these mutants, confirming a tissue-nonautonomous role of Adamtsl2 in bone growth control.
  5. Less surprisingly, tendon cells were disorganised in the mutants, exhibiting a rounded shape and some changes in fibrillin expression, revealing a tissue-autonomous role of Adamtsl2 in tendon structure.

What I like about this preprint

It is quite clear that this study’s initial focus was on human disease, but ended up shedding light on a fundamental biological mechanism, namely the coordination of growth between the tissues composing an organ. Kudos to the authors for embracing the new research direction. It is refreshing to see how curiosity always finds its way.

Pending questions

  1. How does tendon structure influence bone growth? While they don’t rule out paracrine signalling (akin to the one we described between the infrapatellar fat pad and the growth plate [2]), the authors hypothesise that the effect is mechanical, such that a shorter tendon exerts compressive forces on the growing bone, limiting its growth. This hypothesis could be easily tested by resecting the Achilles tendon in control and mutant pups, so that the compressive forces are relieved before the phenotype arises.
  2. What is the role of soft tissues other than tendons? The authors show that deleting Adamtsl2 in all soft tissues not only impairs bone growth, but also leads to a wider shaft, whereas deleting Adamtsl2 only in the tendons does not affect bone width. This suggests that different tissues exert distinct influences on bone growth.
  3. Is the observed effect specific to Adamtsl2 or a general consequence of loss of tendon integrity? It would be interesting to induce cell death in tendons, to address whether another way of inducing shortening also impairs bone growth. The potential role of inlflammation could be relevant to human injuries.

Related research

  1. Longobardi et al. 2012. Dev. Cell.
  2. Rosello-Diez et al. 2017. eLife.
  3. Logan et al. 2002. Genesis.

Tags: bone growth, mouse, soft tissues, tendons, tissue crosstalk

Read preprint (No Ratings Yet)




  • Have your say

    Your email address will not be published. Required fields are marked *

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    Human macrophages survive and adopt activated genotypes in living zebrafish

    Colin D. Paul, Alexus Devine, Kevin Bishop, et al.



    Selected by Giuliana Clemente

    Altering the temporal regulation of one transcription factor drives sensory trade-offs

    Ariane Ramaekers, Simon Weinberger, Annelies Claeys, et al.



    Selected by Mariana R.P. Alves

    Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry

    Natalia A Shylo, Dylan A Ramrattan, Scott D Weatherbee



    Selected by Hannah Brunsdon

    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.



    Selected by Andreas van Impel

    1

    Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

    Jovany Jeomar Franco, Youmna Maryline Atieh, Chase Dallas Bryan, et al.



    Selected by Helen Weavers

    Photoperiod sensing of the circadian clock is controlled by ELF3 and GI

    Usman Anwer, Amanda Davis, Seth Jon Davis, et al.



    Selected by Annika Weimer

    A non-cell autonomous actin redistribution enables isotropic retinal growth

    Marija Matejcic, Guillaume Salbreux, Caren Norden



    Selected by Yara E. Sánchez Corrales

    1

    Rearing temperature and fatty acid supplementation jointly affect membrane fluidity and heat tolerance in Daphnia

    Dominik Martin-Creuzburg, Bret L. Coggins, Dieter Ebert, et al.



    Selected by Alexander Little

    A SoxB gene acts as an anterior gap gene and regulates posterior segment addition in the spider Parasteatoda tepidariorum

    Christian L. B. Paese, Anna Schoenauer, Daniel J. Leite, et al.



    Selected by Erik Clark

    1

    Cell type-specific interchromosomal interactions as a mechanism for transcriptional diversity

    Adan Horta, Kevin Monahan, Lisa Bashkirova, et al.



    Selected by Boyan Bonev

    Germ layer specific regulation of cell polarity and adhesion gives insight into the evolution of mesoderm.

    Miguel Salinas-Saavedra, Amber Q. Rock, Mark Q. Martindale



    Selected by ClaireS & SophieM

    1

    Wnt/β-catenin regulates an ancient signaling network during zebrafish scale development

    Andrew J Aman, Alexis N Fulbright, David M Parichy



    Selected by Andreas van Impel

    Tissue flow induces cell shape changes during organogenesis

    Gonca Erdemci-Tandogan, Madeline J.Clark, Jeffrey D. Amack, et al.



    Selected by Jacky G. Goetz

    Temporal Control of Transcription by Zelda in living Drosophila embryos

    Jeremy Dufourt, Antonio Trullo, Jennifer Hunter, et al.



    Selected by Teresa Rayon

    1

    An atlas of silencer elements for the human and mouse genomes

    Naresh Doni Jayavelu, Ajay Jajodia, Arpit Mishra, et al.



    Selected by Rafael Galupa

    1

    Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct

    Scott D Findlay, Olena Bilyk, Kiefer Lypka, et al.



    Selected by Pierre Osteil

    Also in the genetics category:

    A robust method for transfection in choanoflagellates illuminates their cell biology and the ancestry of animal septins

    David Booth, Heather Middleton, Nicole King



    Selected by Maya Emmons-Bell

    SWI/SNF remains localized to chromatin in the presence of SCHLAP1

    Jesse R Raab, Keriayn N Smith, Camarie C Spear, et al.



    Selected by Carmen Adriaens

    1

    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.



    Selected by Andreas van Impel

    1

    Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

    Jovany Jeomar Franco, Youmna Maryline Atieh, Chase Dallas Bryan, et al.



    Selected by Helen Weavers

    Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

    Dirk Hubmacher, Stetson Thacker, Sheila M Adams, et al.



    Selected by Alberto Rosello-Diez

    Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ)

    Scott J Callahan, Stephanie Tepan, Yan M Zhang, et al.



    Selected by Hannah Brunsdon

    1

    PDX Finder: A Portal for Patient-Derived tumor Xenograft Model Discovery

    Nathalie Conte, Jeremy Mason, Csaba Halmagyi, et al.



    Selected by Carmen Adriaens

    Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

    Jacob Daane, Jennifer Lanni, Ina Rothenberg, et al.



    Selected by Alberto Rosello-Diez

    1

    Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of cell division, differentiation, and loss

    Judy Martin, Erin Nicole Sanders, Paola Moreno-Roman, et al.



    Selected by Natalie Dye

    F-actin patches nucleated on chromosomes coordinate capture by microtubules in oocyte meiosis

    Mariia Burdyniuk, Andrea Callegari, Masashi Mori, et al.



    Selected by Binyam Mogessie

    Comprehensive characterization of transcript diversity at the human NODAL locus

    Scott D Findlay, Lynne-Marie Postovit



    Selected by Christian Ramos

    Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

    Alberto Rosello-Diez, Linda Madisen, Sebastien Bastide, et al.



    Selected by Natalie Dye

    Precise temporal regulation of alternative splicing during neural development

    Sebastien M Weyn-Vanhentenryck, Huijuan Feng, Dmytro Ustianenko, et al.



    Selected by James Gagnon

    Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

    Claudio Cantù, Anastasia Felker, Dario Zimmerli, et al.



    Selected by Andreas van Impel

    Insect wings and body wall evolved from ancient leg segments

    Heather S Bruce, Nipam H Patel

    AND

    Two sets of wing homologs in the crustacean, Parhyale hawaiensis

    Courtney M Clark-Hachtel, Yoshinori Tomoyasu



    Selected by Erik Clark

    2

    Close

    We want to make our website, and the services we provide, useful and reliable. This sometimes involves placing small amounts of information called cookies on the device you used to access the internet. If you continue to use this website we will assume you are happy to accept our cookies.

    Accept