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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-Cre^ERT2 ::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.

SUBMITTER: Wong SA

PROVIDER: S-EPMC8451921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:After reduction of complex mandibular fractures, contouring of the fracture plates to fixate the reduced mandibular segments can be time-consuming. Objective:To explore the potential application of a 3-dimensional (3-D)-printed short-segment mandibular template in the management of complex mandibular fractures. Design, Setting, and Participants:A feasibility study was performed at a tertiary academic center using maxillofacial computed tomography data of 3 patients with comminuted mandibular fractures who required preoperative planning with a perfected complete mandible model. Interventions:Thresholding, segmentation, and realignment of the fractured mandible were performed based on computed tomography data. Each reduced mandible design was divided to create 3-D templates for 6 fracture sites: right and left angle, body, and symphyseal/parasymphyseal. Sessions were conducted with junior otolaryngology and plastic surgery residents, during which mandibular fracture plates were contoured in a "preoperative" setting against the 3-D-printed short-segment templates, and an "intraoperative" setting against the previously manufactured, complete mandible model. The previously manufactured, complete model served as a surrogate for the intraoperative mandible with the fracture site reduced. Main Outcomes and Measures:The time for 3-D template printing, the "preoperative" (measure of the time consumed preoperatively), and "intraoperative" (measure of the time saved intraoperatively) times were recorded. Comparisons were made for cost estimates between a complete model and the 3-D-printed short-segment template. The operating room charge equivalent of the intraoperative time was also calculated. Results:Of the 3 patients whose data were used, 1 was a teenager and 2 were young adults. The total time for 3-D modeling and printing per short-segment template was less than 3 hours. The median (range) intraoperative time saved by precontouring the fracture plates was 7 (1-14), 5 (1-30), and 7 (2-15) minutes, and the operating room charge equivalents were $350.35 ($50.05-$700.70), $250 ($50.05-$1501.50), and $350.35 ($100.10-$750.75) for the angle, body, and symphyseal/parasymphyseal segments, respectively. The total cost for a single 3-D-printed template was less than $20, while that for a perfected complete model was?approximately?$2200. Conclusions and Relevance:We demonstrate that patient- and site-specific 3-D-printed short-segment templates can be created within the timeframe required for mandibular fracture repair. These novel 3-D-printed templates also demonstrate cost efficiency in the preoperative planning for complex mandibular fracture management compared with perfected models and facilitate plate contouring in a similar fashion. Estimation of reduced operative room cost and time with the application of these short-segment templates warrants studies in actual patient care. Level of Evidence:NA.

Project description:In response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development. However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing in mice. Constitutive YAP and/or TAZ deletion from Osterix-expressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture or by developmental deficiencies in the progenitor cell pool before fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset-inducible knockout mice (using Osx-CretetOff ) in which YAP and TAZ were deleted before fracture but after normal development. Adult onset-induced YAP/TAZ deletion had no effect on cartilaginous callus formation but impaired bone formation at 14 days post-fracture (dpf). Earlier, at 4 dpf, adult onset-induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset-induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf before the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. © 2020 American Society for Bone and Mineral Research (ASBMR).

Project description:Mandibular fracture repair is complicated by limited availability of bone as well as the presence of the neurovascular bundle and an abundance of tooth roots. Fractures at the location of the mandibular first molar teeth are common and it can be particularly challenging to apply stable fixation. Non-invasive fracture repair techniques utilize intraoral placement of fixation devices typically involving polymerized composites and/or interdental wiring. A novel calcium phosphate-phosphoserine-based mineral-organic adhesive was tested ex vivo to determine its effects on augmenting strength of different non-invasive fracture fixation techniques. This study both tested the use of mineral-organic adhesive for the purpose of stabilizing currently used non-invasive fracture repair constructs (intraoral composite splinting ± interdental wiring) and evaluated adhesive alone or with subperiosteally placed plates on buccal cortical bone surface. Aside from controls, not receiving an osteotomy along the mesial root of the mandibular first molar tooth, six treatment groups were tested to evaluate ultimate strength, stiffness, angular displacement, bending moment, and application time. All forms of fixation were found to be significantly weaker than control (p < 0.001). Only the control (p < 0.001) and mineral-organic adhesive and composite (P = 0.002) groups were found to be significantly stronger than wire and composite. No difference was noted in stiffness between any groups with control or wire and composite. Application times varied from the mineral-organic adhesive group (mean = 206 s) to mineral-organic adhesive and composite (mean = 1,281 s). Twenty-three fixation devices exhibited adhesive failure, 20 demonstrated cohesive failure, and 5 failed by cohesive and adhesive failure. When evaluating the ultimate strength of the fixation device groups, mineral-organic adhesive, and composite was shown to be the strongest construct. The use of resorbable bone adhesive and composite may provide a stronger fixation construct over interdental wire and composite for mandibular fracture repair in dogs.

Project description:To gain insight into the effect of diabetes on fracture healing, experiments were carried out focusing on chondrocyte apoptosis during the transition from cartilage to bone. Type 1 diabetes was induced in mice by multiple low-dose streptozotocin injections, and simple transverse fractures of the tibia or femur was carried out. Large-scale transcriptional profiling and gene set enrichment analysis were performed to examine apoptotic pathways on total RNA isolated from fracture calluses on days 12, 16, and 22, a period of endochondral bone formation when cartilage is resorbed and chondrocyte numbers decrease. Tumor necrosis factor alpha (TNF-alpha) protein levels were assessed by ELISA and caspase-3 by bioactivity assay. The role of TNF was examined by treating mice with the TNF-specific inhibitor pegsunercept. In vitro studies investigated the proapoptotic transcription factor FOXO1 in regulating TNF-induced apoptosis of chondrogenic ATDC5 and C3H10T1/2 cells as representative of differentiated chondrocytes, which are important during endochondral ossification. mRNA profiling revealed an upregulation of gene sets related to apoptosis in the diabetic group on day 16 when cartilage resorption is active but not day 12 or day 22. This coincided with elevated TNF-alpha protein levels, chondrocyte apoptosis, enhanced caspase-3 activity, and increased FOXO1 nuclear translocation (p < .05). Inhibition of TNF significantly reduced these parameters in the diabetic mice but not in normoglycemic control mice (p < .05). Silencing FOXO1 using siRNA in vitro significantly reduced TNF-induced apoptosis and caspase activity in differentiated chondrocytes. The mRNA levels of the proapoptotic genes caspase-3, caspase-8, caspase-9, and TRAIL were significantly reduced with silencing of FOXO1 in chondrocytic cells. Inhibiting caspase-8 and caspase-9 significantly reduced TNF-induced apoptosis in chondrogenic cells. These results suggest that diabetes causes an upregulation of proapoptotic genes during the transition from cartilage to bone in fracture healing. Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-alpha, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation.

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Chondrocyte-to-osteoblast transformation in mandibular fracture repair.

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