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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

Posted on: 30 May 2018

Preprint posted on 24 April 2018

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

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