Chondrocyte-to-osteoblast transformation in mandibular fracture repair.

Sarah A Wong,Joshua Slocum,Theodore Miclau,Chelsea S Bahney,Ralph S Marcucio,Charles Lam,Michael Nguyen,Diane P Hu

doi:10.1002/jor.24904

Abstract

The majority of fracture research has been conducted using long bone fracture models, with significantly less research into the mechanisms driving craniofacial repair. However, craniofacial bones differ from long bones in both their developmental mechanism and embryonic origin. Thus, it is possible that their healing mechanisms could differ. In this study we utilize stabilized and unstabilized mandible fracture models to investigate the pathways regulating repair. Whereas fully stable trephine defects in the ramus form bone directly, mechanical motion within a transverse fracture across the same anatomical location promoted robust cartilage formation before boney remodeling. Literature investigating long bone fractures show chondrocytes are a direct precursor of osteoblasts during endochondral repair. Lineage tracing with Aggrecan‐CreERT2::Ai9 tdTomato mice demonstrated that mandibular callus chondrocytes also directly contribute to the formation of new bone. Furthermore, immunohistochemistry revealed that chondrocytes located at the chondro‐osseous junction expressed Sox2, suggesting that plasticity of these chondrocytes may facilitate this chondrocyte‐to‐osteoblast transformation. Based on the direct role chondrocytes play in bone repair, we tested the efficacy of cartilage grafts in healing critical‐sized mandibular defects. Whereas empty defects remained unbridged and filled with fibrous tissue, cartilage engraftment produced bony‐bridging and robust marrow cavity formation, indicating healthy vascularization of the newly formed bone. Engrafted cartilage directly contributed to new bone formation since a significant portion of the newly formed bone was graft/donor‐derived. Taken together these data demonstrate the important role of chondrocyte‐to‐osteoblast transformation during mandibular endochondral repair and the therapeutic promise of using cartilage as a tissue graft to heal craniofacial defects.

Highlights

Craniofacial bones differ from appendicular bones in both their embryonic origin and developmental mechanism.[1]
In this study we aimed to study the role of chondrocyte‐to‐osteoblast transformation during mandible fracture repair by utilizing two mandible fracture models: a stabilized trephine defect model that heals via intramembranous ossification, and an unstabilized osteotomy that heals via endochondral ossification
Despite differences in embryonic origin and developmental mechanism, our study demonstrates that mandibular fractures proceed through conserved mechanisms of repair as seen in long bones

Summary

Introduction

Craniofacial bones differ from appendicular bones in both their embryonic origin and developmental mechanism.[1] Appendicular bones are derived from lateral plate mesoderm through the process of endochondral ossification This process begins with the differentiation of mesenchymal stem cells into chondrocytes that form a cartilage template in the approximate size and shape of the future bone. The cartilage anlage is eventually converted to bone.[2] In contrast, craniofacial bones develop from the cranial neural crest through the process of intramembranous ossification. Unlike endochondral ossification, this process does not involve a cartilage intermediate. To optimize current treatments and develop novel therapies for craniofacial fractures, improving our mechanistic understanding of specific fracture types is critical

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