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

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 trajectoryreveals 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 interorgan growth coordination.

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

“…The wrn −/− mutant zebrafish displayed stunted bone formation in the fish as early as 7 dpf, which might be caused by impairments in the elongation of bones. Longitudinal bone elongation is the engine of human stature growth 34 , which is a coordinated and orchestrated process including three main types of chondrocytes: resting, proliferative, and hypertrophic chondrocytes 50 , 51 . Previously, WRN was shown to be crucial for cell growth; most of the Hela cells were arrested in S-phase when the WRN protein was dysfunctional 52 .…”

Functions of the SNAI family in chondrocyte‐to‐osteocyte development

“…The formation of skeletal elements begins with a common path driven by different chondrogenic and osteogenic programs. 1 Briefly, after induction, preskeletal mesenchymal cells express the calciumdependent adhesion molecule N-cadherin, which is required for cell-cell interactions. Fibroblast growth factor-β (FGF-β) promotion of the expression of fibronectin and neural cell adhesion molecule (N-CAM) begins the aggregation state of cells required for preskeletal condensation.…”

“…The formation of skeletal elements begins with a common path driven by different chondrogenic and osteogenic programs 1 . Briefly, after induction, preskeletal mesenchymal cells express the calcium‐dependent adhesion molecule N‐cadherin, which is required for cell–cell interactions.…”