title: Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance.
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.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Stern
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rona
authors.initials: R
authors.lastname: Aviram
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Chagai
authors.initials: C
authors.lastname: Rot
authors.affiliation: Department of Statistics and Operations Research, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Galili
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Laboratory of Bone Biomechanics, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food & Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Amnon
authors.initials: A
authors.lastname: Sharir
authors.affiliation: Laboratory of Bone Biomechanics, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food & Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Noga
authors.initials: N
authors.lastname: Kalish Achrai
authors.affiliation: Faculty of Engineering, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Yosi
authors.initials: Y
authors.lastname: Keller
authors.affiliation: Laboratory of Bone Biomechanics, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food & Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Shahar
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elazar
authors.initials: E
authors.lastname: Zelzer
mesh_terms: D000818:Animals; D050280:Arm Bones / Q000000981:diagnostic imaging / Q000196:embryology* / Q000254:growth & development*; D001846:Bone Development / Q000502:physiology*; D021621:Imaging, Three-Dimensional; D007867:Leg Bones / Q000000981:diagnostic imaging / Q000196:embryology* / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015233:Models, Statistical; D055114:X-Ray Microtomography