Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis

Abstract

SUMMARYThe vertebrate skeleton consists of over 200 individual bones, each with its own unique shape, size and function. We study the role of intrauterine muscle-induced mechanical loads in determining the three-dimensional morphology of developing bones. Analysis of the force-generating capacity of intrauterine muscles in mice revealed that developing bones are subjected to significant and progressively increasing mechanical challenges. To evaluate the effect of intrauterine loads on bone morphogenesis and the contribution of the emerging shape to the ability of bones to withstand these loads, we monitored structural and mineral changes during development. Using daily micro-CT scans of appendicular long bones we identify a developmental program, which we term preferential bone growth, that determines the specific circumferential shape of each bone by employing asymmetric mineral deposition and transient cortical thickening. Finite element analysis demonstrates that the resulting bone structure has optimal load-bearing capacity. To test the hypothesis that muscle forces regulate preferential bone growth in utero, we examine this process in a mouse strain (mdg) that lacks muscle contractions. In the absence of mechanical loads, the stereotypical circumferential outline of each bone is lost, leading to the development of mechanically inferior bones. This study identifies muscle force regulation of preferential bone growth as the module that shapes the circumferential outline of bones and, consequently, optimizes their load-bearing capacity during development. Our findings invoke a common mechanism that permits the formation of different circumferential outlines in different bones.

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

“…In those territories there is little muscle mass to provide a vector for distortion of shape. Alterations in the timing and quality of mineralization of developing long bones is associated with modification in the shape of long bones, including bent bones and fractures of the diaphysis (Sharir at al., 2011). The data evaluated for this review are consistent with bent bones seen in both humans and mice with poor ossification due to altered FGFR2 dysplasia (Merrill et al, 2012).…”

Combining Coherent Hard X-Ray Tomographies with Phase Retrieval to Generate Three-Dimensional Models of Forming Bone

“…Initially, after the non-mineralized osteoid matrix starts to mineralize, bone material in both formation and healing conditions appears as a highly porous structure, where mineralized and soft tissue are intermixed. Such early formed bone tissues gradually transform and rearrange into solid cortical bone that eventually takes on the appearance of the mature tissue (Miller et al, 2007;Manjubala et al, 2009;Lange et al, 2011;Preininger et al, 2011;Sharir et al, 2011 Vetter et al, 2011;Rohrbach et al, 2013;Bortel et al, 2015). The early formed tissue morphology is thus transient and contains zones of markedly different morphologies, e.g., woven bone and lamellar bone, such that different degrees of mineralization are observed in adjacent bone sites at the same developmental timepoint.…”

“…Detailed information about both architecture and density is thus necessary for understanding and possibly predicting bone growth and tissue repair. Much insight into the temporal and spatial events taking place during skeletal development has come from ex vivo experiments, with important contributions from mouse models (e.g., Richman et al, 2001;Nowlan et al, 2010;Sharir et al, 2011). A handful of studies have focused on understanding the morphogenesis and structural changes that the initially templated bone structures undergo.…”

“…Bortel et al (2015) observed condensation occurring in the midshaft cortex within 14 days after birth. Sharir et al (2011) examined neonatal shape formation in the C57BL/6 mice strain limbs and observed a temporary cortical asymmetric thickening with preferred zones developing mineralized struts on the periosteal side. By comparing their results to findings in a mutant mouse (mdg) strain that lacks skeletal muscle contractility, Sharir et al (2011) proposed that intrauterine muscle forces have an important effect on the shape of the prenatal bones.…”

“…Sharir et al (2011) examined neonatal shape formation in the C57BL/6 mice strain limbs and observed a temporary cortical asymmetric thickening with preferred zones developing mineralized struts on the periosteal side. By comparing their results to findings in a mutant mouse (mdg) strain that lacks skeletal muscle contractility, Sharir et al (2011) proposed that intrauterine muscle forces have an important effect on the shape of the prenatal bones. Other studies support the assumption that muscle activity guides shape formation in bone development, as observed for example in mouse mutant models with targeted muscle immobilization (Nowlan et al, 2010;Sharir et al, 2013).…”