Cranial Base Synchondrosis Lacks PTHrP-Expressing Column-Forming Chondrocytes

Abstract

The cranial base contains a special type of growth plate termed the synchondrosis, which functions as the growth center of the skull. The synchondrosis is composed of bidirectional opposite-facing layers of resting, proliferating, and hypertrophic chondrocytes, and lacks the secondary ossification center. In long bones, the resting zone of the epiphyseal growth plate houses a population of parathyroid hormone-related protein (PTHrP)-expressing chondrocytes that contribute to the formation of columnar chondrocytes. Whether PTHrP+ chondrocytes in the synchondrosis possess similar functions remains undefined. Using Pthrp-mCherry knock-in mice, we found that PTHrP+ chondrocytes predominantly occupied the lateral wedge-shaped area of the synchondrosis, unlike those in the femoral growth plate that reside in the resting zone within the epiphysis. In vivo cell-lineage analyses using a tamoxifen-inducible Pthrp-creER line revealed that PTHrP+ chondrocytes failed to establish columnar chondrocytes in the synchondrosis. Therefore, PTHrP+ chondrocytes in the synchondrosis do not possess column-forming capabilities, unlike those in the resting zone of the long bone growth plate. These findings support the importance of the secondary ossification center within the long bone epiphysis in establishing the stem cell niche for PTHrP+ chondrocytes, the absence of which may explain the lack of column-forming capabilities of PTHrP+ chondrocytes in the cranial base synchondrosis.

Cranial Base Synchondrosis: Chondrocytes at the Hub

“…However, the exact relationship between the SOC and this growth plate stem cell population remains to be elucidated. In our recent study, we examined the presence of a Pthrp -expressing stem cell population in synchondroses [ 42 ]. Surprisingly, Pthrp expressing cells were found predominantly within a wedge-shaped structure on the lateral borders of the SOS.…”

Augmentation of bone morphogenetic protein signaling in cranial neural crest cells in mice deforms skull base due to premature fusion of intersphenoidal synchondrosis

“…Different with majority skull bones are formed via intermembranous ossification, in which mesenchymal cells differentiate into osteoblasts to form bones (Nakashima & de Crombrugghe, 2003), bones in the cranial base are developed by endochondral ossification, which cartilage are replaced into bones, similar with bones in the trunk and extremities (Rengasamy Venugopalan & Van Otterloo, 2021; Young et al, 2006). Unlike endochondral ossification in the long bones, synchondroseal growth is bidirectional (Bailleul & Horner, 2016; Hallett et al, 2022). We recently reported that a feedback loop between Indian hedgehog and parathyroid hormone‐related protein (PTHrP) plays critical roles in the posterior‐to‐anterior ossification of cartilage primordia in the cranial base (Zhang et al, 2022).…”

“…We recently reported that a feedback loop between Indian hedgehog and parathyroid hormone‐related protein (PTHrP) plays critical roles in the posterior‐to‐anterior ossification of cartilage primordia in the cranial base (Zhang et al, 2022). Interestingly, however, PTHrP‐expressing cells, which contribute to formation of columnar chondrocytes in long bones, do not contribute to the formation of columnar structures in synchondrosis (Hallett, Zhou, et al, 2022). These facts suggest that there are different molecular cellular mechanisms of endochondral ossification between the cranial base and the long bones.…”

Pth1r Signal in Gli1+ Cells Maintains Postnatal Cranial Base Synchondrosis

“…Thus, any abnormalities of the synchondroses could affect skull and midfacial morphologies (Wei et al 2016; Funato 2020). A recent review identified Runt-related transcription factor 2 (RUNX2), the T-box transcription factor family 1 (TBX1), the fibroblast growth factor receptor family (FGFRs), the parathyroid hormone–related protein (PTHrP) pathway, the Indian hedgehog (IHH) pathway, the cilium assembly, and the Wnt/β-catenin pathway as some of the factors regulating synchondrosis development (Wei et al 2016; Funato 2020; Hallett, Ono, et al 2022; Hallett, Zhou, et al 2022).…”