Abstract Tooth and alveolar bone health are essential for proper oral functions of feeding, chewing, speaking, and other essential activities of daily life. Alveolar bone loss due to periodontitis and tooth cracking are the second and third most common reasons for tooth loss. Elucidating the molecular regulation of dentin synthesis and alveolar osteogenesis will contribute to filling the significant knowledge gap and finding new molecules to target for therapeutics. The runt related transcription factor 2 (Runx2) is the master regulator of skeletogenesis. Humans harboring mutations in the RUNX2 gene exhibit cleidocranial dysplasia, which is characterized by both dental and various skeletal anomalies. Global deletion of Runx2 gene in mice results in complete failure of ossification and embryonic lethality. Our previous work has demonstrated that Runx2 is required for the differentiation of the resting chondrocytes to hypertrophic chondrocytes and endochondral ossification. We have also shown that Runx2 gene deletion in developing osteoblasts impairs the postnatal synthesis of long bone and the acquisition of adult bone mass. Our preliminary data show a surprisingly significant increase in dentin synthesis in mice with Runx2-deficient odontoblasts and a concomitant decrease in bone synthesis and bone mass by Runx2-deficient osteoblasts. Furthermore, the microenvironments of alveolar osteoblasts compared to long bone osteoblasts are fundamentally different. These osteoblasts have different origins, pathogen exposure, and loading forces. Therefore, we hypothesize that Runx2 is required for postnatal dentin synthesis and alveolar osteogenesis. We further postulate that the gene expression profiles of alveolar and long bone osteoblasts are fundamentally different. We will experimentally test these hypotheses in the following proposed aims: In Aim 1, we plan to elucidate the regulatory role of Runx2 in committed odontoblasts for dentin synthesis. Aim 2 is focused on determining the critical differences in Runx2 regulated alveolar and long bone osteogenesis. The proposed experiments will utilize unique mouse models to answer fundamental mechanistic questions about the differential regulation of dentin and alveolar bone synthesis by Runx2. This application builds on a strong interdisciplinary scientific environment and institutional support to train successful clinician-scientists in the field of oral and maxillofacial regeneration. This combination is necessary for my goals of becoming an independent researcher as an oral and maxillofacial surgeon-scientist. The findings from the proposed experiments will uncover Runx2-regulated pathways that could serve as therapeutic targets for dentin and alveolar bone repair and regeneration. Additionally, understanding the functional differences between alveolar and long bone osteoblasts will enhance craniofacial and orthopedic therapies.