Macrophage depletion in male mice impairs extraction socket healing by disrupting bone regeneration and tissue repair

Abstract

Objectives

Macrophages play a critical role in tissue repair and bone regeneration by regulating inflammation, angiogenesis, and osteoblast differentiation. The present study examined the role of macrophages in extraction socket healing using a clodronate liposome-induced macrophage depletion model in mice, with a focus on both soft and hard tissue regeneration. We also investigated the involvement of cytokines, such as TGF-β, PDGF, and BMP2.

Design

Male C57BL/6 J mice were intravenously administered clodronate or control liposomes three days prior to tooth extraction and the healing process was analyzed by histology, immunohistochemistry, RNA in situ hybridization, and quantitative RT-PCR.

Results

The clodronate liposome treatment significantly reduced F4/80-positive and CD206-positive macrophages, delayed mucosal closure, disrupted angiogenesis, and suppressed new bone formation. Vascular density in the extraction socket was significantly reduced, and was accompanied by decreases in the expression of PDGF-A and PDGF-B, which are critical for mesenchymal stem cell migration and angiogenesis. The expression of BMP2 and TGF-β and their downstream signaling were also suppressed, which impaired new bone formation.

Conclusion

These results demonstrate that macrophages are essential for the cytokine-mediated coordination of soft and hard tissue regeneration and highlight their therapeutic potential to improve periodontal and bone regeneration treatments. Because all experiments were performed in male C57BL/6 mice, these findings may not fully extend to females, in which estrogen is known to modulate macrophage function and bone healing.