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.

Highlights

  • The three-dimensional (3D) morphology of bones is fundamental to the ability of an organism to move, feed, and protect itself

  • Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation

  • By analyzing a massive database of micro-computed tomography (CT) images of developing mouse long bones, we show that all superstructures maintain their relative positions throughout development

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Summary

Introduction

The three-dimensional (3D) morphology of bones is fundamental to the ability of an organism to move, feed, and protect itself. Most bones develop by endochondral ossification, a process whereby an anlage of cartilage roughly in the shape of the future bone is formed and gradually replaced by mineralized tissue [1,2,3,4,5]. The replacement of cartilage by ossified tissue is regulated by the growth plates, which are composed of chondrocytes that maintain a tightly controlled dynamic balance between proliferation and differentiation. The two growth plates continuously replace cartilage with ossified tissue while moving away from each other. This causes a gradual increase in the length of the bone [6] until maturity is reached and elongation ceases

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