Periodontal disease is an inflammatory disease caused by periodontopathogenic bacteria, which eventually leads to bone tissue (alveolar bone) destruction as inflammation persists. Periodontal tissues have an immune system against the invasion of these bacteria, however, due to the persistent infection by periodontopathogenic bacteria, the host innate and acquired immunity is impaired, and tissue destruction, including bone tissue destruction, occurs. Osteoclasts are essential for bone destruction. Osteoclast progenitor cells derived from hematopoietic stem cells differentiate into osteoclasts. In addition, bone loss occurs when bone resorption by osteoclasts exceeds bone formation by osteoblasts. In inflammatory bone disease, inflammatory cytokines act on osteoblasts and receptor activator of nuclear factor-κB ligand (RANKL)-producing cells, resulting in osteoclast differentiation and activation. In addition to this mechanism, pathogenic factors of periodontal bacteria and mechanical stress activate osteoclasts and destruct alveolar bone in periodontitis. In this review, we focused on the mechanism of osteoclast activation in periodontitis and provide an overview based on the latest findings.

Human periodontal ligament mesenchymal stem cells (hPDLMSCs) have been known that they play important roles in homeostasis and regeneration of periodontal tissues. Additionally, spheroids are superior to monolayer-cultured cells. We investigated the characteristics and potential of periodontal tissue regeneration in co-cultured spheroids of hPDLMSCs and human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Co-cultured spheroids were prepared with cell ratios of hPDLMSCs: HUVECs = 1:1, 1:2, and 2:1, using microwell chips. Real-time polymerase chain reaction (PCR) analysis, Enzyme-Linked Immuno Sorbent Assay (ELISA), and nodule formation assay were performed to examine the properties of co-cultured spheroids. Periodontal tissue defects were prepared in the maxillary first molars of rats and subjected to transplantation assay. The expression levels of stemness markers, vascular endothelial growth factor (VEGF), osteogenesis-related genes were up-regulated in co-cultured spheroids, compared with monolayer and spheroid-cultured hPDLMSCs. The nodule formation was also increased in co-cultured spheroids, compared with monolayer and spheroid cultures of hPDLMSCs. Treatment with co-cultured spheroids enhanced new cementum formation after 4 or 8 weeks of transplantation, although there was no significant difference in the new bone formation between co-cultured spheroids and hPDLMSC spheroids. We found that co-cultured spheroids enhance the periodontal tissue regeneration. Co-cultured spheroids of hPDLMSCs and HUVECs may be a useful therapy that can induce periodontal tissue regeneration.