Clinical and Scientific Innovations for Oral and Maxillofacial Surgery (CSIOMS)


Osteo Science Foundation Featured Speakers & Abstracts

Marco C. Bottino, DDS, MSc, PhD, FADMMarco C. Bottino, D.D.S., MSc., Ph.D., FADM Peter Geistlich Research Grant Winner
University of Michigan, Ann Arbor, United States

Title: Biofabrication Technologies for Personalized Craniomaxillofacial Tissue Regeneration 

For nearly three decades, tissue engineering strategies have been leveraged to devise effective therapeutics for craniomaxillofacial tissue regeneration. In this regard, additive manufacturing (AM) allows the fabrication of personalized scaffolds that have the potential to recapitulate native tissue morphology and biomechanics through the utilization of several 3D printing techniques. Among these, melt electrowriting (MEW) offers great prospects for the fabrication of scaffolds mimicking tissue specificity, personalized multi-scale transitions, and functional interfaces. This presentation will describe innovative and emerging MEW-driven strategies to engineer personalized and tissue-specific scaffolds for regeneration of hard and soft craniomaxillofacial tissues.

Sarah Anne Wong, DDS, PhDSarah Wong
University of California, San Francisco

Title: β-Catenin/Wnt Signaling is Critical to Chondrocyte-to-Osteoblast Transformation during Fracture Repair in the Craniofacial and Appendicular Skeletons

Bone fractures represent a significant health burden with over 15 million new fractures occurring in the United States each year.1 The majority of fractures heal through the process of endochondral ossification in which a cartilage callus intermediate forms between the fractured bone ends and is gradually replaced with bone. In the biological context of long bone development and growth, it has been shown the chondrocytes of the cartilage anlage directly convert into osteoblasts and give rise to new bone.2–4 However, there is debate whether chondrocyte-to-osteoblast transformation occurs during endochondral fracture repair and the molecular regulatory mechanisms that govern this process remain largely unknown.

Canonical Wnt signaling is a prime regulatory candidate due to its role in promoting osteogenesis. Inhibition of this pathway in mesenchymal precursor cells inhibits calvarial bone development and instead results in ectopic cartilage formation.5 In contrast, over-activation of this pathway has been shown to increase bone formation in models of intramembranous repair.6 Preliminary data from our lab also indicate that canonical Wnt signaling may play a role during chondrocyte-to-osteoblast transformation in the context of endochondral repair. Indeed, callus chondrocytes in the region of chondrocyte transformation show nuclear localization of β-catenin, an indicator of active Wnt signaling. We hypothesized that chondrocytes transform into osteoblasts during endochondral repair and that canonical Wnt signaling is a key regulator of this process.

Chondrocyte lineage tracing was performed using inducible Aggrecan Cre or Col10 Cre mice with a dTomato reporter. Mandible fractures were made via osteotomy of the right ramus from the anterior border of the coronoid process to the anterior border of the angular process. Tibia fractures were made in the mid-diaphysis of the right tibia via 3-point-bending. Cre recombination was induced with tamoxifen (D6-10). Samples were harvested (D14), cryosectioned, and evaluated with epifluorescent microscopy (N=3-4/model). To determine the role of canonical Wnt signaling in chondrocyte transformation, the pathway was conditionally inhibited or over-activated in chondrocytes by deleting or stabilizing β-catenin, respectively. Fractures and Cre recombination were performed as above. Histology and stereology were performed following harvest (D7,10,14,21) to quantify tissue composition (N=5/group/timepoint).

Lineage tracing using both Aggrecan and Col 10 Cre drivers confirmed that chondrocyte-to-osteoblast transformation occurs during endochondral repair and that the contribution of chondrocytes to new bone formation is significant. Regarding canonical Wnt pathway regulation of chondrocyte transformation, inhibition of this pathway in chondrocytes through deletion of β-catenin resulted in significantly reduced bone formation and increased cartilage retention compared to controls. Conversely, gain-of-function Wnt signaling through β-catenin stabilization in chondrocytes significantly increased bone formation and simultaneously reduced cartilage callus composition at early time points, indicating both increased and accelerated chondrocyte-to-osteoblast transformation.

Together, our data show that chondrocyte-to-osteoblast transformation occurs during endochondral repair and that canonical Wnt signaling is critical to this process. These findings lend key insight regarding our understanding of endochondral repair and suggest new therapeutic targets for fracture healing.


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