Project Summary/Abstract
Trauma- and cancer-induced tissue damage is common in the mandible. Critical failures associated with current
grafting treatments, like osteonecrosis, occur due to poor local conditions and limited integration between the
graft and the host tissue. Recent studies show that cartilage grafts produce well-vascularized and integrated
bone regeneration similar to an isograft, indicating that chondrocytes can form bones. As a mechanism, cell
trans-differentiation from chondrocytes into bone cells has been demonstrated. Yet, membranous osteogenesis
is currently considered the sole mechanism in the formation and repair of mandible body, despite two types of
cartilage (Meckel’s cartilage, MC; and Rostral Process, RP) present during mandible growth. Similar to the
mouse model, a RP-MC-like structure is identified in human fetuses and infants. To address whether
endochondrogenesis contributes to the growth and repair of mandible body, a series of studies using
complementary approaches has been performed. The key findings are: 1) the mandible body is composed of
both membranous and endochondral bones; 2) hypertrophic chondrocytes in MC and RP directly trans-
differentiate to bone cells instead of directly entering apoptosis; 3) RP-MC is one continuous cartilage; 4) a new
Condensed Mesenchymal Progenitor (CMP) zone is identified, which provides new cell sources for RP and MC
expansion; and 5) endochondrogenesis plays a key function in the mandible repair via a switch mechanism from
the default program (membranous bone) to a trauma repair program (endochondral bone), where
chondrogenesis (with limited requirement of angiogenesis) occurs first, followed by chondrocyte trans-
differentiation into bone. Based on these findings, the central hypothesis is that the mandible body is composed
of both endochondral and membranous bones, and that endochondrogenesis plays a key role in mandible repair.
To test this central hypothesis, three highly related, yet independent Specific Aims are proposed: 1) To determine
how MC and RP contribute to mandible formation via chondrocyte trans-differentiation; 2) To delineate the
mechanism by which RP is derived from the CMP, and the CMP-RP, a growth-plate like structure, converges
and elongates the two ends of MCs during mandible growth at cellular and molecular levels; 3) To determine
how endochondrogenesis contributes to mandible repair via a switch mechanism from the default development
program (membranous bone) to a trauma repair program (endochondral bone) through a change in the stem cell
fate. Completion of this project will 1) demonstrate that the CMP-RP-MC complex contributes to mandible growth
via the trans-differentiation of RP-MC chondrocytes into bone cells; and 2) identify some of key factors that are
responsible for the switch from membranous osteogenesis to endochondrogenesis via a change of the stem cell
fate in the repair process. These results will likely revise the current concept, provide new knowledge in this
largely unknown but vital area, and create a foundation for developing novel approaches, which will ultimately
accelerate future mandible trauma repair processes.