Core binding factor 1 (Cbfa1)/runt-related transcription factor 2 (Runx2) has been identified as a ''master gene'' in osteoblastic differentiation. In this two-part study, part I of the study was undertaken to test the hypothesis that bone regeneration is compromised in Cbfa1+/− mice. Compared with wild-type mice, wound healing was dramatically delayed in Cbfa1+/− mice characterized by the presence of a small amount of bone near the base of the wounds. The bone defects were largely filled with fibrous connective tissues 3 weeks after surgery. Part II was performed to determine the effects of Cbfa1 in enhancing bone wound healing using a gene-activated matrix (GAM) method. Cbfa1 cDNA was mixed with a biodegradable bovine type I collagen sponge and was inserted into the periodontal window wounds of mice. Control sponges were collagen matrix without Cbfa1 cDNA. Histological analysis and immunohistochemical staining demonstrated that compared with controls, there was increased new bone formation that almost filled the wound defects 14 days after surgery in the Cbfa1-GAM group. The collagen sponge matrix did not seem to elicit significant foreign body reaction in either group. In conclusion, the reduced expression of Cbfa1 interferes with the process of bone wound healing, and local application of Cbfa1 cDNA incorporated into a collagen matrix promotes bone tissue regeneration.Millions of Americans are afflicted with periodontal diseases that cause destruction of supporting structures of teeth: periodontal ligament (PDL), alveolar bone, and cementum. The process can lead to the loss of attachment, with destruction of the connective tissue matrix and cells. Loosening and eventual loss of teeth may follow. However, despite considerable research efforts in this area, regeneration of the periodontium has still proved to be an elusive goal of periodontal therapy and remains a subject of intense interest to dentists and dental scientists, with the molecular and cellular bases of PDL formation, repair, and regeneration still poorly understood.In the 1980s, Gould observed that the progenitor cells for cementum, bone, and PDL fibroblasts were all contained in PDL tissue. 1 He described generation of a new, functionally oriented PDL when teeth bearing cultured PDL cells were transplanted into bony sites. By contrast, the transplantation of teeth bearing cultured gingival cells did not lead to regeneration of the PDL. These early studies indicated that regeneration of damaged periodontium can be achieved by Similar to adipocyte 3 and myoblast 4 differentiation, it is apparent that components of the extracellular matrix are also critical for initiating cell differentiation during osteogenesis. 5 In the 1990s, independent studies of a transcription factor that regulated the tissue-specific expression of osteocalcin (OCN) 6,7 and analysis of transgenic knockouts 8,9 resulted in the identification of core-binding factor 1 (Cbfa1), a runt domain transcription factor and its cognate enhancer. This transcription factor, also r...