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Review
. 2019 Nov 20;20(23):5840.
doi: 10.3390/ijms20235840.

Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate

Ryuma Haraguchi  1 , Riko Kitazawa  1   2 , Yukihiro Kohara  1 , Aoi Ikedo  3 , Yuuki Imai  3 , Sohei Kitazawa  1
Affiliations
Review

Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate

Ryuma Haraguchi et al. Int J Mol Sci. .

Abstract

The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the "growth plate", is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any failure in this process causes a wide range of skeletal disorders. Therefore, the cellular and molecular characteristics of the growth plate are of interest to many researchers. Hedgehog (Hh), well known as a mitogen and morphogen during development, is one of the best known regulatory signals in the developmental regulation of the growth plate. Numerous animal studies have revealed that signaling through the Hh pathway plays multiple roles in regulating the proliferation, differentiation, and maintenance of growth plate chondrocytes throughout the skeletal growth period. Furthermore, over the past few years, a growing body of evidence has emerged demonstrating that a limited number of growth plate chondrocytes transdifferentiate directly into the full osteogenic and multiple mesenchymal lineages during postnatal bone development and reside in the bone marrow until late adulthood. Current studies with the genetic fate mapping approach have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence of epiphyseal chondrocyte-derived Hh signals during endochondral bone formation. Here, we discuss the valuable observations on the role of the Hh signaling pathway in the growth plate based on mouse genetic studies, with some emphasis on recent advances.

Keywords: bone disease; chondrocyte; endochondral ossification; growth plate; hedgehog; osteoblast.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Figures

Figure 1
Figure 1
The longitudinal growth of long bone by the growth plate. The growth plate is composed of highly organized and specialized three types of cartilage: the resting, proliferative, and hypertrophic zone. Resting zone chondrocytes supply stem-like cells that give rise to clones of proliferative zone chondrocytes, and determine the spatial orientation of adjacent proliferative columns parallel to the long axis of the bone. The proliferative zone is the region of active cell replication. Hypertrophic zone chondrocytes provide a cartilaginous template, mineralized by their extracellular matrix, supporting the new bone formation by osteoblastic cells. Scale bars indicate 1.25 mm.
Figure 2
Figure 2
Overview of hedgehog signaling pathway. (A) In the absence of Hh ligands, Ptc-1 blocks Hh pathway activation through the repression of Smo. (B) Once the Hh ligand binds to Ptc-1, the repressive action to Smo is released, and Gli-mediated transcription leading to the regulation of downstream target Hh is activated.
Figure 3
Figure 3
Chondrocyte-derived Ihh is required for the maintenance of a normal growth plate. (A,B) Longitudinal view of μCT images in distal femur from control and Gli1-CreER; Ihhc/c (Ihh cKO). Control and Ihh cKO littermate mice were treated with tamoxifen at four weeks of age and analyzed after eight weeks to inactivate the Ihh gene. Note decreased trabecular mass and completely lacked growth plate in Ihh cKO mice (B). (C,D) Representative images of femur stained with hematoxylin and alcian blue. Alcian blue positive cartilage matrix in the distal femur is absent in Ihh cKO mice (D, arrowheads show). Scale bars indicate 1 mm (A,B) and 1.25 mm (C,D).
Figure 4
Figure 4
Loss of β-catenin gene in growth plate derived Hh-signal responded cells results in osteopenia and fatty bone marrow. (A,B) Longitudinal view of μCT images in distal femur from control and Gli1-CreER; β-cateninc/c (β-catenin cKO). Control and β-catenin cKO littermate mice were treated with tamoxifen at 4 weeks of age and analyzed after 10 weeks to inactivate the β-catenin gene. μCT imaging revealed that β-catenin deletion resulted in an abnormal bone formation in the distal femur. (C–F) Representative images of femur stained with hematoxylin and eosin. (E,F) Higher magnification of blue boxes in (C,D). Histology revealed a lack of trabecular bone under the abnormal growth plate of β-catenin cKO mice (D,F). This bone phenotype was likely due to increased osteoclastic bone resorption (F, Asterisks mark increased osteoclasts). Histology of the femur also indicated a significant increase in adipocytes at the metaphysis (F, arrowheads show). Scale bars indicate 1 mm (A,B), 500 μm (C,D) and 50 μm (E,F).
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