Critical Roles of Rostral-Process-Meckel’s-Cartilage in Mandibular Formation and Repairing

Objectives: It is generally accepted that mandibular ossification and regeneration occur via an intramembranous mechanism; and that mandible cartilage is associated but does not directly contribute to bone formation. The goal of this study was to investigate whether and how Rostral Process (RP)-Meckel’s cartilage (MC) directly contributes to mandibular growth and repair.
Methods: To define the cell fate of mouse MC, R26R^Tomato mice were crossed with inducible Gli1-Cre^ERT2 (expressed in early progenitor cells), Aggrecan-Cre^ERT2 (Agr, expressed in all cartilage), or Col10a1-Cre (expressed in hypertrophic chondrocytes) mice, with or without 2.3Col1a1-GFP (expressed in bone cells). Mice were sacrificed from E11.5 (before Meckel’s cartilage) to P28. The combined approaches of in vivo cell lineage-tracing, histology, confocal microscopy, and immunohistochemistry with different cartilage and bone markers were used to determine the contributions of cartilage in mandibular development and repair.
Results: The first sign of intramembranous bone was observed at E13.5 along the mandible dentary. From E15.5, numerous MC-derived bone cells clearly presented with bone markers expression, such as Col I and DMP1, indicating a direct transformation of MC chondrocytes into bone cells in both Col10a1-Cre and Agr-Cre background. Importantly, a separate progenitor niche (Gli1⁺ and Agr⁺, named condensed mesenchymal progenitor, CMP) was identified. Further studies showed that CMPs are responsible for the formation of the RP and expansion of MC during postnatal mandibular growth. In a trauma response, we clearly demonstrated both chondrocyte-derived and non-chondrocyte derived bone cells take part in bone repairing.
Conclusions: 1) The mandibular bone originates from non-cartilage-derived and cartilage-derived bone cells; 2) The CMP-RP-MC, equivalent to a long bone growth plate, is responsible for expansion of the anterior portion of the mandible, including symphysis; and 3) chondrocyte-derived and non-chondrocyte-derived bone cells coordinate for mandibular bone repairing. This work sheds new light on the mandibular development and repair process.