NG2/CSPG4 in Mandibular Endochondral Fracture Healing

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PROJECT SUMMARY/ABSTRACT This application represents a training plan designed to provide mentoring, career development, and support to the applicant as a clinician-scientist seeking to move research from the benchtop to the bedside in craniofacial and oral sciences. The training plan encompasses laboratory experimentation and professional and career development opportunities, and the plan is supported by the outstanding local and institutional resources available at UIC. The proposed research will address an important unmet clinical need facing craniofacial trauma. While the mandible is the strongest and largest facial bone, there is a high level of incidence for mandibular fractures. Unstable mandibular fractures exhibit delayed healing compared to fixed fractures, and their healing involves a chondrocyte-to-osteoblast developmental pathway that is not yet fully understood. Understanding the specific molecular pathways that control fracture resolution is important for improving clinical outcomes and the development of new therapeutics. The focus of this study is on a transmembrane proteoglycan, NG2/CSPG4. This molecule has been implicated in the mechanical response of mandibular chondrocytes in the temporomandibular joint and the progression of osteoarthritis, but it has not been studied in the context of endochondral fracture healing. The research plan in this proposal utilizes a preclinical murine model of endochondral fracture healing in the mandible, together with transgenic knockout animal models, to define the role of NG2/CSPG4 in the cell differentiation cascade that is required for the successful mineralization of a fracture callus. The proposed research plan will test the central hypothesis that mechanical loading-dependent NG2/CSPG4 signaling regulates the differentiation of osteochondral progenitor cells during endochondral ossification in mandibular fractures. Long-term, our goal is to understand how cells make decisions about their fate during bone regeneration. Aim 1 will evaluate the role of NG2/CSPG4 in the ability of osteochondral progenitor cells to differentiate into cartilage. Aim 2 will focus on the role of NG2/CSPG4 in the ability of cartilage cells to undergo mineralization. Together, the data generated from this project will address an important gap in knowledge surrounding mandibular fracture healing and bone biology more broadly and may identify a new therapeutic target for clinical intervention.