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WIREs Dev Biol
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Integrating levels of bone growth control: From stem cells to body proportions

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Abstract The study of the mechanisms controlling organ size during development and regeneration is critical to understanding how complex life arises from cooperating single cells. Long bones are powerful models in this regard, as their size depends on a scaffold made from another tissue (cartilage, composed of chondrocytes), and both tissues interact during the growth period. Investigating long bone growth offers a valuable window into the processes that integrate internal and external cues to yield finely controlled size of organs. Within the cellular and molecular pathways that control bone growth, the regulation of stem‐cell renewal, along with amplification and differentiation of their progeny, are key to understanding normal and perturbed long‐bone development. The phenomenon of “catch‐up” growth–where cellular hyperproliferation occurs following injury to restore a normal growth trajectory–reveals key aspects of this regulation, such as the fact that bone growth is target‐seeking. The control mechanisms that lead to this behavior are either bottom‐up or top‐down, and the interaction between these modes is likely critical to achieve a highly nuanced, yet flexible, degree of control. The role of cartilage‐intrinsic mechanisms has been well studied, establishing a very solid groundwork for this field. However, addressing the unanswered questions of bone growth arguably requires new hypotheses and approaches. Future research could for example address to what extent extrinsic signals and cells, as well as communication with other tissues, modulate intra‐limb and inter‐organ growth coordination. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Vertebrate Organogenesis > Musculoskeletal and Vascular
Steps of endochondral ossification. The different cell types and structures appear color‐coded. The primary ossification center appears in brown, at the center of the element. Secondary ossification centers are not shown
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Two types of top‐down control. (a) Schematic of the growth plate showing potential niches and the mitogens they produce (green arrows). Dashed T‐arrows represent negative feedback exerted by the primary spongiosa or the perichondrium in proportion to bone size/growth rate. (b) Interpretation of catch‐up growth based on mitogen competition model, whereby the niche‐produced mitogen increases the tendency to self‐renew. (c) Sizostat theory, in which the growth rate is proportional to the mismatch between levels of a growth inhibitor and its receptor
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Potential bottom‐up mechanisms of growth control. (a) Example in which the first component (proliferation) of the loop promotes both the second component (density, Hippo activation) and the output, and the second component inhibits the output. (b) Example in which the first component (tissue damage) promotes the second component (injury response or stress signal) but inhibits the outcome. (c) In bottom‐up mechanisms operating by proximity (left), only the neighbors close‐by respond to the defect. In community mechanisms, a self‐regenerating signal creates a chemical wave that travels quickly throughout the organ, leading to a whole‐organ response
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Control of chondrocyte proliferation and differentiation. (a) Main paracrine signaling pathways involved. Two differentiation steps are included: from resting to proliferative and from proliferative to hypertrophic. The name of the different ligands is located near the overall area of expression (perichondrium if outside the cartilage). BMP, bone morphogenetic protein; CNP, C‐natriuretic peptide; FGF, fibroblast growth factor; IGF1, insulin‐like growth factor 1; IHH, indian hedgehog; PTHrP, parathyroid hormone related protein; WNT, wingless‐Int1. (b) The IHH‐PTHrP feedback loop maintains a constant size of the proliferative zone (PZ), by coupling proliferation and differentiation, like a water tank with coupled inlet and outlet valves. Different growth rates (flows) are theoretically possible for the same PZ height
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The steps and regulatory logic acting from stem cells through cartilage and bone. Only the interactions and parameters most likely to affect bone length (as opposed to mass) are shown. For each cell transition i, pi represents the probability of remaining at the original state, while vi represents the speed of transition towards the next state. Negative feedback on p and v is shown as red and black block arrows, while α, β, γ, … and a, b, c, … quantify the extent of feedback
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The four theoretical modes of stem cell regulation. (a–d) Different possible modes of stem cell regulation that result from combining two orthogonal mechanisms of control: internal versus external and individual‐level versus population level. Note that in (d), the displaced cell would have continued being a self‐renewing stem cell had it not been displaced by dividing neighbors. Illustration designed after (Simons & Clevers, 2011b)
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Catch‐up growth is driven by cell‐nonautonomous mechanisms. (a) Schematics of normal and catch‐up bone growth trajectories. (b) Mosaic overexpression of p21 (red ovals) in chondrocytes triggers local compensatory proliferation (arched green arrows showing hyperproliferation) in spared chondrocytes. (c) When one of the growth plates is damaged (yellow), the remote growth plate (green) gives rise to more bone scaffold (striped pattern) than in the undamaged condition
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Vertebrate Organogenesis > Musculoskeletal and Vascular
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing
Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches