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 24 April 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

Posted on: 30 May 2018

Read preprint (No Ratings Yet)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

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

Register here

preLists in the developmental biology category:

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020

 



List by Irepan Salvador-Martinez, Martin Estermann

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

 



List by Sergio Menchero et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

 



List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar

Also in the genetics category:

Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University

This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.

 



List by Nándor Lipták

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill
Close