Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance

PLoS Biol. 2015 Aug 4;13(8):e1002212. doi: 10.1371/journal.pbio.1002212. eCollection 2015 Aug.

Abstract

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of individual epiphyseal plates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arm Bones / diagnostic imaging
  • Arm Bones / embryology*
  • Arm Bones / growth & development*
  • Bone Development / physiology*
  • Imaging, Three-Dimensional
  • Leg Bones / diagnostic imaging
  • Leg Bones / embryology*
  • Leg Bones / growth & development*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Models, Statistical
  • X-Ray Microtomography

Grant support

The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement n° 310098, the Jeanne and Joseph Nissim Foundation for Life Sciences Research, the Irving and Dorothy Rom Charitable Trust, and the Estate of David Levinson. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.