Meckel’s Cartilage Directly Contributes to Early Mandibular Formation

Objectives: It is generally accepted that Meckel’s cartilage, the main component of mandibles in cartilaginous fish, is associated but does not directly contribute to mandibular bone formation in mammals. The goal of this study was to investigate whether and how Meckel’s cartilage directly contributes to the mandibular bone formation.
Methods: To define the cell fate of the mouse Meckel’s cartilage, the ROSA26^-tdTomato mice were separately crossed with the inducible Gli1-Cre^ERT2 (expressed in early progenitor cells) and Aggrecan-Cre^ERT2 (Agr, expressed in all cartilage), and Col X-Cre (expressed in hypertrophic chondrocytes) with or without the 2.3 Col 1-GFP (expressed in bone cells). Animals 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 Meckel’s cartilage in mandibular development.
Results: The first sign of intramembranous bone was observed at E13.5 along the mandible dentary. From E15.5 and after, numerous red (tomato+) bone cells adjacent to Meckel’s cartilage were clearly present and co-expressed bone markers such as Col I and DMP1, indicating a direct transformation from Meckel’s cartilage into mandibular bone in both Col 10-Cre and Agr-Cre^ERT2 background. Importantly, a separate progenitor niche anterior but separated from Meckel’s cartilage (Gli1+ and Agr+) was identified, which transformed into chondrocyte-derived and non-chondrocyte-derived bone cells surrounding the mandibular symphysis postnatally. Later, mandibular bone formation and remodeling was mainly controlled by cells from the periosteum.
Conclusions: The early mandibular bone originates from three cell types: the non-cartilage-derived cells for intramembranous bone, Meckel’s cartilage-derived endochondral ossification, and progenitor cells at the mandible tip surrounding the symphysis. This work challenges the current dogma about the origin of the mandibular bone and contribution of Meckel’s cartilage during early mandibular development.