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Review
. 2016 Oct;95(11):1221-9.
doi: 10.1177/0022034516651823. Epub 2016 Jun 1.

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

X Wei  1 , M Hu  2 , Y Mishina  3 , F Liu  4
Affiliations
Review

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

X Wei et al. J Dent Res. 2016 Oct.

Abstract

Long bones and the cranial base are both formed through endochondral ossification. Elongation of long bones is primarily through the growth plate, which is a cartilaginous structure at the end of long bones made up of chondrocytes. Growth plate chondrocytes are organized in columns along the longitudinal axis of bone growth. The cranial base is the growth center of the neurocranium. Synchondroses, consisting of mirror-image growth plates, are critical for cranial base elongation and development. Over the last decade, considerable progress has been made in determining the roles of the parathyroid hormone-related protein, Indian hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling pathways in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of the primary cilia signaling pathway in bone elongation. Here, we review the development of the growth plate and cranial synchondrosis and the regulation by the above-mentioned signaling pathways, highlighting the similarities and differences between these 2 structures.

Keywords: FGF; Ihh; PTHrP; Wnt; chondrocyte; primary cilia.

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Conflict of interest statement

The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
The cranial base and synchondroses. (A) Micro–computed tomography image of the skeletal structures of the mouse cranial base at 2 mo of age. From the rostral side (right) to the caudal side (left), the cranial base of the mouse is composed of presphenoid, basisphenoid, and basioccipital bone. Between the adjacent bones are cartilaginous synchondroses, namely the intersphenoid synchondrosis (ISS) and the spheno-occipital synchondrosis (SOS). (B) Histological structures of the cranial base in a newborn mouse. Three ossification centers (occipital, basisphenoid, and presphenoid) are separated by 2 synchondroses: the ISS and the SOS. The synchondrosis is composed of mirror-image growth plates with a central resting zone (R), proliferative zones (P), and hypertrophic zones (H) on both sides.
Figure 2.
Figure 2.
Mechanisms of parathyroid hormone–related protein (PTHrP) signaling in chondrocyte maturation. PTHrP can cyclin-D1–dependently induce degradation of runt-related transcription factor 2 and 3 (Runx2/3); down-regulate Runx2 expression through the protein kinase A (PKA) pathway; increase expression of zinc finger transcriptional coregulator 521 (Zfp521), which antagonizes Runx2 through histone deacetylase 4 (HDAC4); and promote dephosphorylation of HDAC4 and thus inhibit myocyte enhancer factor 2C (MEF2C) transcription. P represents phosphorylation.
Figure 3.
Figure 3.
Regulation of parathyroid hormone–related protein (PTHrP)/Indian hedgehog (Ihh) signaling and fibroblast growth factor receptor 3 (FGFR3) signaling on cranial synchondrosis development. (A) PTHrP can maintain chondrocyte proliferation and inhibit their hypertrophic differentiation. Ihh promotes chondrocyte proliferation and maturation and also stimulates PTHrP expression. It is unclear whether Ihh stimulates PTHrP expression as in the growth plate of long bones. (B) Active mutation of FGFR3 suppresses chondrocyte proliferation and down-regulates expression of the PTHrP receptor and Ihh. Premature fusion of synchondroses in FGFR3 mutant mice may be mediated by the mitogen-activated protein kinase (MAPK) pathway.
Figure 4.
Figure 4.
Regulatory mechanisms of Indian hedgehog (Ihh) expression. Both the CCAAT/enhancer binding protein beta (C/EBPβ)/runt-related transcription factor 2 (Runx2) complex and the β-catenin/lymphoid enhancer binding factor 1 (Lef1) complex can bind the Ihh promoter to stimulate Ihh expression. Activating transcription factor 4 (ATF4) can activate Ihh transcription by binding to its promoter. Sirtuin 6 may increase the affinity of ATF4 to the Ihh promoter. δ–EF1, a two-handed zinc finger/homeodomain transcriptional repressor, can inhibit Ihh transcription by binding to Ihh regulatory elements.
Figure 5.
Figure 5.
Mutations leading to the premature fusion of cranial synchondroses. Chondrocyte-specific deletion of Indian hedgehog (Ihh), fibroblast growth factor receptor (FGFR) mutations (FGFR3369/369, FGFR3G374R/+, FGFR3P244R+/+, FGFR3365/+, FGFR2IIIcP253R, FGFR2IIIc−/−, FGFR2P253R/+), and primary cilia signaling dysregulation (loss of Ellis-van Creveld syndrome protein homolog [EVC] and chondrocyte-specific deletion of Kif3a [a component of the Kinesin-II motor complex] or intraflagellar transport 88 [IFT88]) can all lead to the premature fusion of synchondroses in mice.
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