Impact of the host response and osteoblast lineage cells on periodontal disease

Abstract

Periodontitis involves the loss of connective tissue attachment and alveolar bone. Single cell RNA-seq experiments have provided new insight into how resident cells and infiltrating immune cells function in response to bacterial challenge in periodontal tissues. Periodontal disease is induced by a combined innate and adaptive immune response to bacterial dysbiosis that is initiated by resident cells including epithelial cells and fibroblasts, which recruit immune cells. Chemokines and cytokines stimulate recruitment of osteoclast precursors and osteoclastogenesis in response to TNF, IL-1β, IL-6, IL-17, RANKL and other factors. Inflammation also suppresses coupled bone formation to limit repair of osteolytic lesions. Bone lining cells, osteocytes and periodontal ligament cells play a key role in both processes. The periodontal ligament contains cells that exhibit similarities to tendon cells, osteoblast-lineage cells and mesenchymal stem cells. Bone lining cells consisting of mesenchymal stem cells, osteoprogenitors and osteoblasts are influenced by osteocytes and stimulate formation of osteoclast precursors through MCSF and RANKL, which directly induce osteoclastogenesis. Following bone resorption, factors are released from resorbed bone matrix and by osteoclasts and osteal macrophages that recruit osteoblast precursors to the resorbed bone surface. Osteoblast differentiation and coupled bone formation are regulated by multiple signaling pathways including Wnt, Notch, FGF, IGF-1, BMP, and Hedgehog pathways. Diabetes, cigarette smoking and aging enhance the pathologic processes to increase bone resorption and inhibit coupled bone formation to accelerate bone loss. Other bone pathologies such as rheumatoid arthritis, post-menopausal osteoporosis and bone unloading/disuse also affect osteoblast lineage cells and participate in formation of osteolytic lesions by promoting bone resorption and inhibiting coupled bone formation. Thus, periodontitis involves the activation of an inflammatory response that involves a large number of cells to stimulate bone resorption and limit osseous repair processes.

Keywords: bone remodeling; gingiva; growth factor; lymphocyte; osseous; osteogenic; periodontal ligament; stromal.

Figure 1

Regulation of bone and the impact of inflammation. Mesenchymal stem cells (MSCs) can differentiate into multiple lineages and are regulated by growth and differentiation factors that induce transcriptional programs that are lineage-specific. Osteoclasts are of myeloid lineage. Inflammation promotes osteoclastogenesis, in part, by inducing osteocytes to produce chemokines, inflammatory cytokines and RANKL. Inflammation also reduces coupled bone formation by inducing osteoblasts/osteocytes to produce inhibitors of Wnt signaling, DKK2 and sclerostin, interfering with differentiation at several steps, limiting the production of bone matrix, osteoid, and inducing apoptosis of mesenchymal stem cells, OB progenitors, OB and osteocytes. Thus, bone lining cells, OB and osteocytes play an important role in maintaining periodontal bone mass through secreting factors that regulate the balance of osteoclastogenesis and osteogenesis.

Figure 2

Single cell analysis indicates identifies distinct fibroblastic/stromal, epithelial and immune cell sub-populations. When subjected to transcriptional analysis, several distinct clusters can be identified within the major groups of cells isolated from healthy and inflamed gingiva, suggesting specialized function. When compared to healthy tissue, gingiva associated with periodontal inflammation exhibits a decrease in several epithelial populations (but an increase in inflammatory epithelial cells, an increase in neutrophils and B-cells, and a decrease in fibroblasts/stromal cells (but an increase in inflammatory fibroblasts). The various cell populations from each major group respond to challenge and interact to generate an inflammatory host response. This table was adapted from information in ref: (138) and (140).