Biomarking the Sclerostin Antibody Effects on Osseointegration in an Osteogenesis Imperfecta Model

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Project Summary/abstract Osteogenesis Imperfecta is a genetic dysplasia characterized by brittle bone, increased bone fracture and low bone density. Current OI management relies mainly upon long-term anti-resorptive treatments that prevent fractures, yet may interfere with normal jaw bone healing. A novel strategy for OI treatment is Sclerostin Antibody (SclAb), which induces a strong anabolic response to increase bone density. Although SclAb increases bone formation and significantly improves the biomechanical long bone properties, long-term continuous dosing rapidly decreases bone-formation response by increasing Wnt antagonist expression. Cycling SclAb treatments with antibody-free periods restores bone-formation response based on long bone research, so little is known how this strategy affects jaw bone and implant osseointegration (bone healing). Successful implant stability (primary healing) and osseointegration (long-term healing) depends on good bone density. Therefore, to predict jaw bone density in OI before and after implant placement, there is a clinical need to biomark SclAb-induced anabolic effects. The use of MicroRNAs (miRNAs) as biomarkers for OI is attractive. Found to play key roles in the regulation of bone homeostasis-related pathways, bone-remodeling-related miRNAs may possibly replace the current nonspecific bone density diagnosis tools, resulting in a personalized medicine approach for OI treatment management. There are 2 aims in this study. Aim 1: Elucidate the optimal SclAb-cycle therapy regimen that induces and sustains the jawbone formation response and its effect on osseointegration. Aim 2: To determine the bone-remodeling-related miRNA panels that detect or predict SclAb treatment outcome to guide implant placement decisions. The results of this proposal will provide both the SclAb therapy schedule that induces and sustains the optimal bone anabolic effects without affecting the healing and miRNA panels of anabolic and resorptive phase that can be used to correlate the SclAb effects on bone metabolism for dental and orthopedic treatment decisions and long-term disease monitoring of low bone mass patients. The candidate is firmly committed to a career in developing effective, clinically applicable orofacial bone regeneration strategies to improve the quality of life among low bone mass disorder patients. Her Mentor, Advisory Committee Members and the Oral and Maxillofacial Surgery Department at the University of Michigan School of Dentistry strongly support the candidate and her career and research goals. She currently holds a position as an Assistant Professor with 20% protected time for her PhD research project. The proposed experiments and didactic work will position her with a unique set of cross-disciplinary skills, enabling her transition to independence as a surgeon-scientist with a focus in Translational Craniofacial Regenerative Medicine.