Cranial Base Synchondrosis: Chondrocytes at the Hub

Abstract

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, both in the neural crest and mesoderm. In humans, premature ossification of the synchondroses causes midfacial hypoplasia, which commonly presents in patients with syndromic craniosynostoses and skeletal Class III malocclusion. Major signaling pathways and transcription factors that regulate the long bone growth plate-PTHrP-Ihh, FGF, Wnt, BMP signaling and Runx2-are also involved in the cranial base synchondrosis. Here, we provide an updated overview of the cranial base synchondrosis and the cell population within, as well as its molecular regulation, and further discuss future research opportunities to understand the unique function of this craniofacial skeletal structure.

Keywords: chondrocyte(s); cranial base; craniofacial development; endochondral ossification; osteoblast; regeneration; skeleton; synchondrosis.

Figure 1

Morphology of cranial base and SOS harvested at postnatal day 28 from C57BL/6 mouse. (A). Gross morphology of dissected cranial base positioned in an anteroposterior manner. (B). Sagittal section of ISS, basi-sphenoid bone and SOS. (C). Magnified image highlighting bidirectional arrangement of chondrocyte layers in SOS stained with hematoxylin and eosin and presence of presumptive central hypertrophic chondrocytes. Ant: anterior, NS: nasal septum, PS: pre-sphenoid, BS: basi-sphenoid, Post: posterior, ISS: inter-sphenoid synchondrosis, SOS: spheno-occipital synchondrosis, R: resting zone, P: proliferating zone, H: hypertrophic zone, PS: primary spongiosa.

Figure 2

Molecular regulation of the postnatal cranial base synchondrosis. PTHrP-Ihh feedback regulates activity of proliferating chondrocytes until their differentiation into pre-hypertrophic cells. Prickle, a component of the Wnt/PCP pathway, directs asymmetric division of resting cells into adjacent columnar chondrocytes. Fgfr1, Fgfr2 and Fgfr3 expression in proliferating chondrocytes directly controls cranial base elongation. Activating mutations in each receptor are associated with various forms of syndromic craniosynostoses, which commonly present midfacial hypoplasia. Evc2 expression is localized in a gradient-like fashion, wherein which levels increase in the anterior most portions of the SOS and ISS are indirectly regulated through Hedgehog signaling. This relationship instructs posterior-to-anterior differentiation and eventual mineralization of cranial base chondrocytes in addition to formation of the segmented cranial base bones. Ddr2 expression is found in a gradient fashion, with highest levels localized to resting cells. Currently established in the long bone growth plate, Fgfr3-Mapk-Runx2 signaling is a critical component regulating both chondrocyte proliferation and hypertrophy. Whether this relationship exists in the cranial base synchondrosis remains to be elucidated. ISS: inter-sphenoid synchondrosis, SOS: spheno-occipital synchondrosis, R: resting zone, P: proliferating zone, H: hypertrophic zone, PS: primary spongiosa.