Chondrocyte‐to‐osteoblast transformation in mandibular fracture repair

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.

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

“…This has been enabled in part by modern genetic labeling of cells for fate mapping. Our work and others has now clearly demonstrated that chondrocytes give rise to the new bone during repair of fractures in appendicular and facial bones (Bahney et al 2019;Kaji et al 2020;Wong et al 2021). Chondrocytes also contribute to the osteoblast lineage during long bone development.…”

The role of hypertrophic chondrocytes in regulation of the cartilage-to-bone transition in fracture healing

“…Induction of Cre recombination in aggrecan-expressing chondrocytes by tamoxifen at day 7 postfracture demonstrates that their progenies have become Col1a1-expressing osteoblasts ( Zhou et al, 2014 ). This transition of hypertrophic chondrocytes to osteoblasts is also observed in mandibular fractures in mice ( Wong et al, 2021 ).…”

“…It has long been thought that terminally differentiated hypertrophic chondrocytes in endochondral bone formation undergo apoptosis when cartilage is replaced by bone. However, accumulating evidence shows that a substantial number of hypertrophic chondrocytes can survive in the callus and become osteoblasts ( Bahney et al, 2014 ; Scammell and Roach, 1996 ; Wong et al, 2021 ; Yang et al, 2014 ; Zhou et al, 2014 ). Bahney et al (2014) demonstrated presence of host chondrocyte-derived bone cells in a bone grafting model.…”

The Formation of the Epiphyseal Bone Plate Occurs via Combined Endochondral and Intramembranous-Like Ossification

“…Likewise, chondrocytes located at singular sites like the border of the cartilage rudiments and the bony collar [ 44 ], the closing growth plate of aged rats [ 29 ], or the mixed spicules during fracture healing [ 45 ] differentiate according to uncommon ways and gives rise to exceptional phenotypes [ 46 ]. Even the long time accepted idea that hypertrophic chondrocytes are programmed to die during the process of endochondral ossification has been revised by recent studies using lineage tracing techniques that have identified different models for chondrocyte-to-osteoblast transdifferentiation [ 33 , 47 , 48 , 49 ]. In this way, results in the present study support the possibility that chondrocytes may be contribute to the formation of the epiphyseal bone plate.…”