Abstract
A joint connects two or more bones together to form a functional unit that allows different types of bending and movement. Little is known about how the opposing ends of the connected bones are developed. Here, applying various lineage tracing strategies we demonstrate that progenies of Gdf5-, Col2-, Prrx1-, and Gli1-positive cells contribute to the growing epiphyseal cartilage in a spatially asymmetrical manner. In addition, we reveal that cells in the cartilaginous anlagen are likely to be the major sources for epiphyseal cartilage. Moreover, Gli1-positive cells are found to proliferate along the skeletal edges toward the periarticular region of epiphyseal surface. Finally, a switch in the mechanism of growth from cell division to cell influx likely occurs in the epiphyseal cartilage when joint cavitation has completed. Altogether, our findings reveal an asymmetrical mechanism of growth that drives the formation of epiphyseal cartilage ends, which might implicate on how the articular surface of these skeletal elements acquires their unique and sophisticated shape during embryonic development.
Highlights
Synovial joints are structures located between adjacent skeletal elements, allowing different types of locomotion
We noticed that the Gdf5positive cells specified at all the time points tested, except at E14.5 for the elbow joint, exhibited an uneven distribution pattern between the two opposing ends of the knee and elbow joints; where significantly more growth differentiation factor 5 (Gdf5)-traced cells and their progenies were observed in the epiphyseal cartilage of the distal end of femur/humerus compared to the proximal end of tibia/radius (Figures 1A–I and Supplementary Figures S2A–I)
Using various lineage tracing strategies, our work builds on top of the existing influx model of joint development to quantitatively demonstrate the asymmetrical engagement of progenies of the Gdf5, collagen type 2 (Col2), Paired related homeobox 1 (Prrx1), and Gli1-positive cells into the generation of new cartilage at the epiphyseal ends
Summary
Synovial joints are structures located between adjacent skeletal elements, allowing different types of locomotion. The joint surface is covered by articular cartilage and is mechanically stabilized by ligaments that connect the skeletal elements together. Limb formation starts from a continuous and uninterrupted Y-shaped cartilaginous anlagen (Hamrick, 2001). The first sign that marks the initiation of the joint formation process is the accumulation of a condensed mesenchymal cell population at the future joint site within the anlagen, so-called the interzone. Cells within the interzone express a new set of genes, including the growth differentiation factor 5 (Gdf5) and serve as joint progenitors by generating a continuous influx of newly produced cells into the developing joint (Koyama et al, 2008; Shwartz et al, 2016)
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