The Role of nBMP2 in Macrophage Oral Immunomodulation

Periodontal regeneration and bone repair involve classical elements of wound healing and have been perennially met with challenges of inconsistency and predictability. Among the gaps in knowledge regarding periodontal regeneration is how macrophage polarization and function influence periodontal regeneration and bone repair. We and others have defined a central role for the macrophage in the successful regeneration of bone and the periodontium. However, there remains an undefined role for bone morphogenetic protein 2 (BMP2) and nuclear BMP2 – an under characterized BMP2 isoform – in macrophage immunomodulation that supports successful regeneration. We have observed extensive nuclear localization of BMP2 in macrophages cultured on nanoscale topographies and noted that nuclear BMP2-positive macrophages have an M2-like (regenerative) phenotype. In addition, nBMP2 knockout leads to a decrease in STAT6 expression in macrophages and an increase in ligature-induced periodontal bone loss. Combined with Alphafold 3 predictive results and our initial immunoprecipitation data, we will investigate the overarching hypothesis that macrophage nBMP2 and BMP2 expression positively influences macrophage M2 polarization and tissue regeneration via modulation of STAT6 activity. The specific aims are: AIM 1: to characterize the regulation of macrophage nBMP2/BMP2 expression. AIM 2: to functionally dissect nBMP2-regulated STAT6 signaling pathways in macrophages. AIM 3: to demonstrate the role of macrophage nBMP2/BMP2 on tissue repair and regeneration. Using cell culture and knockout mouse models of macrophage nBMP2 and BMP2 expression, and defined models of periodontal regeneration and bone repair, the present study will define the mechanism by which nuclear BMP2 controls macrophage polarization and how macrophage nBMP2/BMP2 expression contributes to bone and periodontal regeneration. The proposed mechanistic studies will be critical for understanding how macrophages contribute to immunomodulation in tissue regeneration, particularly in periodontal regeneration and bone repair. Furthermore, new insights into the physiologic regulation of macrophage function and polarization can extend beyond periodontal regeneration to other tissues, as well as their role in cancer as tissue-associated macrophages. Project Number: 1R56DE035564-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Huizhi Wang | Institution: VIRGINIA COMMONWEALTH UNIVERSITY, RICHMOND, VA | Award Amount: $310,500 | Activity Code: R56 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11532999