Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation

Abstract

Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP–PPR system during root morphogenesis and tooth eruption.

Cellular and molecular mechanisms of tooth root development

“…Previous studies have indicated that CNC-derived cells contribute to mesenchymal tissues during early development (Chai et al, 2000), although there have been limited studies using genetic cell lineage tracing to demonstrate the dynamic contribution of CNC-derived cells specifically during root formation. Recently, however, using an inducible Cre line, researchers have found that osterix (Sp7)-positive mesenchymal cells contain progenitor cells that contribute to different mesenchymal cell types during root development (Ono et al, 2016). We have also recently generated a Pax9-CreER line that can specifically target the CNC-derived mesenchyme in order to follow its contribution to different mesenchymal cell types during root formation (Feng et al, 2016).…”

“…For example, Bmp, Tgfβ, and their mediator Smad4, as well as Shh, Msx2 and Dlx2, are expressed in HERS cells (Åberg et al, 1997;Huang et al, 2010;Lezot et al, 2000;Nakatomi et al, 2006;Yamashiro et al, 2003). In the CNC-derived dental mesenchyme adjacent to the HERS, there is expression of Gli1, Nfic, Fgf, Tgfβ, Bmp, Wnt and its inhibitors, as well as PTHrP/PPR (Pthlh/Pth1r) (Huang et al, 2010;Ono et al, 2016;Steele-Perkins et al, 2003;Wang et al, 2013). In addition, some signaling molecules are expressed in both the HERS and the CNC-derived dental mesenchyme .…”

“…4) through mesenchymal-epithelial interactions during root formation . A recent study has shown that PTHrP/PPR inhibits Nfic expression in the CNCderived mesenchyme during root formation and that loss of this inhibition leads to a root development defect (Ono et al, 2016), suggesting that Nfic is another factor that must be regulated precisely in order to ensure normal root formation.…”

Parathyroid hormone‐related peptide (1–34) promotes tooth eruption and inhibits osteogenesis of dental follicle cells during tooth development

“…As a result of posttranslation processing, PTHrP could generate a variety of fragments, including PTHrP (1–34), PTHrP(38–94), and PTHrP (107–139) peptide (Mangin et al, ; Thiede, Strewler, Nissenson, Rosenblatt, & Rodan, ). N‐terminal PTHrP (1–34) plays an important role in tooth and bone development (Ono et al, ). Mid‐region PTHrP (38–94) affects the placental calcium transport (Kovacs et al, ).…”

BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

“…Osx potentially marks dental mesenchymal progenitors that differentiate into odontoblasts and produce mineralized dentin matrix . We noticed that conditional disruption of Bmpr1a using a constitutively active Osx‐Cre results in embryonic lethality (data not shown) and thus we decided to use an inducible (Tet‐off) system to activate Cre activity during postnatal development.…”