Periodontium-derived fibroblasts as a model to evaluate inflammation and pharmacological modulation of osteogenesis and osteoclast formation

Two anatomically and functionally distinct populations of periodontium-derived fibroblasts can be identified: gingiva fibroblasts (GFs), which originate from the soft connective tissue of the gingiva and support epithelial attachment and tissue integrity, and periodontal ligament fibroblasts (PDLFs), which produce collagenous fibers that anchor teeth within the alveolar bone socket. Both cell types can contribute to osteogenesis when cultured in the presence of mineralization medium, and both cell types can drive osteoclast formation when co-cultured with osteoclast precursors. Under inflammatory conditions such as periodontitis, this balance is disturbed, leading to more osteoclast-driven bone resorption. The model system of osteogenesis and osteoclastogenesis can be used to further dissect the contributing factors of periodontitis by incorporating bacteria or their components like TLR agonists. Chronic inflammation can further be mimicked by using inflammatory cytokines such as IL-1β, TNF-α and Activin-A. Furthermore, bone anabolic and (anti-)catabolic medications such as parathyroid hormone (PTH), anti-TGF-β, sclerostin and anti-sclerostin can be used to investigate their effects on both osteogenesis and osteoclastogenesis. This platform is ideal for studying the effect of medication used in comorbidities of periodontitis, such as rheumatoid arthritis (RA; e.g., anakinra, infliximab) and diabetes (e.g., metformin), which have all been shown to inhibit osteoclast formation. The osteogenesis culture system can be manipulated over time, making it an ideal system for studying how the osteogenic stage of periodontium-derived fibroblasts affects subsequent osteoclast formation. Finally, fibroblast-based three-dimensional (3D) culture systems provide physiologically relevant environments that capture spatial cell-matrix interactions essential for hard and soft tissue repair in periodontal tissue regeneration. Collectively, these models help bridge in vitro findings toward optimized regenerative strategies.