LPS is considered the primary causative agent responsible for the extensive destruction of deep periodontal tissue and periodontal disease [62,63]. LPS is typically comprised of three domains: lipid A, a short-core oligosaccharide, and the O-antigen [64]. Lipid A, also referred to as endotoxin, represents the bioactive portion of LPS and is recognized by the innate immune system [65]. Upon the recognition of LPS, the innate immune system initiates an immune response aimed at eliminating bacterial intruders [66]. LPS can directly induce osteoclastogenesis and bone resorption in vitro and in vivo in mice and rats. Numerous studies have shown that the direct application of LPS to periodontal tissues induces alveolar bone resorption by osteoclasts, resembling the bone loss observed in periodontitis [67,68]. Jiang et al. [69] showed that LPS derived from Escherichia coli and P. gingivalis prompted the generation of osteoclasts from mouse leukocytes. Furthermore, LPS derived from E. coli- and A. actinomycetemcomitans-enhanced receptor activator of nuclear factor kappa-Β ligand (RANKL) expression in periodontal ligament cells (PDLCs), and the addition of LPS increased the count of osteoclasts formed [70,71]. In vitro osteoclastogenesis assays often use LPS derived from bacterial species such as E. coli, P. gingivalis and A. actinomycetemcomitans. To better reflect the pathogenesis of periodontitis and alveolar bone destruction, LPS derived from periodontal bacteria have been increasingly used in in vivo and in vitro models [72,73].

PGN, the primary cell wall component of gram-positive bacteria, can stimulate the production of inflammatory cytokine [74]. PGN activates the host’s innate immune system and induces the release of cytokines, which trigger off the activation of osteoclasts [75,76]. Takenori et al. [77] showed that PGN from Actinomyces naeslundii-induced inflammatory cytokine production and activated osteoclast formation in co-cultures of mouse bone marrow cells and stromal PA6 cells. However, the effects of PGN on osteoclast differentiation can depend on the bacterial species and other factors. Takami et al. [78] discovered that PGN derived from Staphylococcus aureus inhibited the initial stage of osteoclast differentiation when RANKL was present. Meanwhile, Jiang et al. [79] showed that PGN from S. aureus alone did not induce osteoclast formation. These findings suggest that PGN has similar effects to LPS on osteoclast formation and may play a vital role in the pathogenesis of periodontitis.

Gingipains, which are cysteine proteinases of P. gingivalis, are a major group of virulence factors secreted by this periodontopathogenic bacterium. Gingipains are the products of three genes, two of which code for an arginine-specific proteinase (RgpA and RgpB) and one for a lysine-specific proteinase (Kgp) [80]. Previous studies have shown that serum IgG antibodies in patients with periodontitis are primarily reactive to the hemagglutinin/adhesin region of Kgp and RgpA [81,82]. Additionally, Kimito et al. [83] showed that among the antigens produced by P. gingivalis, serum IgG levels in patients with periodontitis were the highest against recombinant RgpA. Furthermore, the N-terminus of recombinant RgpA was found to be the most suitable antigen for screening patients with periodontitis. Gingipains also cause immune response dysregulation and inflammation and promote the interactions between P. gingivalis and other periodontal pathogens, facilitating their survival and biofilm formation [84,85]. Furthermore, gingipains play a key role in immune regulation by endowing P. gingivalis with the ability to evade host immune responses and immune clearance [86]. Moreover, gingipains are involved in the progression of bone loss in periodontitis. In a co-culture system in which gingipains were added to osteoblasts and osteoclast progenitor cells for an osteoclastogenesis assay, the results showed that treatment with Rgp did not alter the number of osteoclasts, but treatment with Kgp promoted osteoclastogenesis [87].

Periodontitis is a chronic inflammatory disease that affects the underlying supporting alveolar bone and soft tissue surrounding the teeth [88,89,90]. Its pathophysiology has been characterized at the molecular level, and it ultimately triggers the activation of host-derived proteinases that enable marginal periodontal ligament fiber loss and apical migration of the junctional epithelium, and allow for the apical spread of the bacterial biofilm along the root surface [91]. In the 1999 International Workshop on Classification of Periodontal Diseases, researchers recommended the unique features of different periodontitis phenotypes and recognized four different forms of periodontitis [92]. Over the past two decades, researchers, clinicians, and epidemiologists have updated the definition of periodontal disease and provided a more refined understanding of periodontal disease staging and grading. The World Symposium 2017 proposed a new classification system for periodontitis that considers both the severity and complexity of periodontitis management. This new system includes four stages of periodontitis, ranging from stage I (initial periodontitis) to stage IV (advanced periodontitis), based on the extent and severity of periodontal tissue damage and the complexity of the treatment required [91]. Severe periodontitis is a highly prevalent chronic disease that has affected approximately 750 million people worldwide over the past three decades, making it the sixth most prevalent chronic disease among the general population [93]. If left untreated, periodontitis can lead to the continual destruction of tooth-supporting tissues, eventually resulting in tooth loss and a consequent decrease in oral function. Finally, it can affect people’s ability to chew, leading to nutritional deficiencies and potential systemic health consequences [3].

Ageing is a time-dependent process that is characterized by the progressive impairment of biological processes in living organisms [5,6]. Studies have shown that ageing is a major risk factor for most chronic diseases and that these diseases restrict the quality of life, independence, and prosperity of older adults [94]. Age-related multimorbidity is a major health concern for older adults, with more than 70% of the people aged over 65 years suffering from two or more chronic disorders such as diabetes, cancer, heart disease, periodontitis, and stroke, accounting for 66.66% of all deaths each year [95]. Periodontitis affects approximately 50% of the world’s adult population, and its prevalence and severity increase with age [7,8,96]. The risk of developing periodontitis increases at approximately 30–40 years of age and is exacerbated in most adults aged over 50 years [5,9]. Among adults aged over 65 years, periodontitis stands as the primary factor behind tooth loss, resulting in significant detriments to masticatory function, aesthetics, and overall quality of life [9].

Cellular senescence is a fundamental phenomenon characterized by irreversible growth arrest, which can be induced by replicative exhaustion or a range of stressors, such as DNA damage, oxidative stress, and inflammation [97]. The induction of the senescent phenotype can be triggered by DNA-damaging stimuli, such as ionizing radiation, oxidative stress, and inflammation [98,99,100]. Senescent cells can release pro-inflammatory cytokines and growth factors, thereby contributing to chronic inflammation and tissue damage in the ageing body. p16^INK4A, p53^INK4B, p21^CIP1 and β-galactosidase are some common biomarkers of senescent cells and are widely used to identify senescent cells [101]. Senescent cells are mainly found at sites of age-related pathologies [102]. In periodontitis, senescent cells accumulate chronologically in the alveolar bone and contribute to age-related alveolar bone deterioration [103,104]. PDLCs, which are a type of mesenchymal stem cells isolated from the periodontal ligament, play an important role in supporting the collagenous fibers in the dense connective tissue of the tooth and in maintaining periodontal homeostasis and replenishing damaged cells during the healing of dental injuries [105]. Moreover, PDLCs constitute a heterogeneous group of cells exhibiting different stages of differentiation and lineage commitment and include periodontal ligament stem cells (PDLSCs), PDLCs and periodontal ligament fibroblasts [106,107]. Recent studies have shown that PDLCs and PDLSCs are similar in terms of their surface marker expression, multipotent differentiation, and regeneration capabilities. These findings suggest that PDLCs may be analogous to PDLSCs and have the potential to differentiate into various cell types [108]. However, the viability and osteogenic differentiation potential of PDLCs have been shown to decline with age [105]. Aged PDLCs exhibit diminished viability and reduced osteogenic differentiation capacity, potentially contributing to the development, and progression of age-related periodontal diseases.

The SASP is characterized by a formidable and intricate group of pro-inflammatory cytokines, chemokines, and proteases secreted by senescent cells. This enigmatic group of molecules collectively orchestrates a profound and dynamic alteration of the local environment, leaving an indelible mark on the surrounding tissue [109,110]. In clinical settings, various inflammatory cytokines and chemokines are identified in the gingival tissue from patients with periodontitis. These biomarkers are indicative of the host’s dysregulated immune response to the subgingival biofilm and are involved in the pathogenesis of periodontitis. IL-1β, IL-6, TNF-α and IFN-γ have been identified as key players in the pathogenesis of periodontitis. These cytokines are produced by immune cells in response to the subgingival biofilm and can cause tissue damage and bone resorption in the periodontium [111]. As previously mentioned, the level of IL-1β increases in patients with periodontitis compared to its level in healthy subjects [112]. Epithelial cells, lymphocytes, and macrophages are the primary sources of IL-6 secretion, triggered by bacterial LPS, IL-1, and TNF-α, and it stimulates osteoclast formation in vitro [113]. TNF-α enhances the expression of IL-1β, IL-6, and RANKL; however, its level in the gingival crevicular fluid (GCF) does not considerably differ before and after periodontitis treatment [114].

In periodontitis, IL-8 and monocyte chemoattractant protein-1 (MCP-1) attract neutrophils and other leucocytes to the inflammation site. IL-8 is produced by macrophages and epithelial cells in response to the presence or stimulation of IL-1β, TNF-α, and LPS [115,116]. Studies have shown that IL-8 enhances osteoclast differentiation and activity, and recruits polymorphonuclear neutrophils to the inflammation site [117]. Furthermore, elevated IL-8 levels have been observed in the GCF of patients diagnosed with chronic periodontitis compared with periodontally healthy control sites [118]. Macrophages, epithelial cells, and T cells secrete MCP-1 in response to bacterial components, including inflammatory mediators or LPS [119]. The MCP-1 level in the GCF decreases after periodontal treatment, compared with levels during periodontitis (at the affected sites), indicating a reduction in the inflammatory response [120,121].

Alveolar bone loss is a hallmark of periodontitis. The alveolar bone, recognized as a dynamic and highly regulated tissue, assumes a crucial function in providing support to the teeth and maintaining their proper position within the maxillofacial skeleton [122]. Alveolar bone remodeling is a complex process that is influenced by a range of mechanical, nutritional, and hormonal factors. The homeostasis between bone formation and resorption is critical for maintaining the structural integrity and function of the alveolar bone. This homeostasis is regulated by a range of hormones and cytokines, which coordinate the coupled process of bone formation and resorption to maintain the alveolar bone volume in healthy persons [123,124,125]. However, in periodontitis, the disruption of homeostasis results in the progressive loss of alveolar bone. The incidence of periodontitis rises with ageing. Although aging itself does not directly cause periodontitis, it can exert an influence on the periodontal milieu, potentially affecting the process of bone resorption and coupling. Ageing is associated with an increase in the production of cytokines that stimulate osteoclastogenesis and inhibit osteoblastic bone formation, leading to an imbalance in bone remodeling [126]. In addition, ageing can lead to changes in hormone levels and nutritional status, which can further exacerbate the imbalance between bone formation and resorption. Ageing-related loss of alveolar bone and periodontal attachment are not necessarily separate processes from periodontitis. Instead, ageing may exacerbate the loss of alveolar bone and periodontal attachment occurring in older adults with periodontitis, leading to more severe disease and poorer outcomes [127,128,129].

Periodontitis is characterized by a perturbation of the delicate balance between bone formation and resorption. The immune responses facilitated by periodontal tissues can trigger T-cell activation and subsequent immune cell accumulation in periodontal lesions, leading to local inflammation and bone damage caused by osteoclasts [130]. In 2000, Arron et al. [131] introduced the concept of osteoimmunology, which describes the intricate interplay between the immune and skeletal systems. Osteoclasts and osteoblasts play a pivotal role in bone remodeling, and their interactions with immune cells involve the secretion of cytokines as well as direct cell–cell contact [132]. Dominant osteoclast activity is the primary cause of alveolar bone loss. Upon activation, osteoclasts adhere to the bone surface and engage with various hormones, cytokines, and proteases to break down the bone mineral matrix, leading to the loss of alveolar bone tissue [49]. Resident cells like fibroblasts, keratinocytes, and dendritic cells secrete inflammatory cytokines that promote the migration of numerous inflammatory cells, including neutrophils, macrophages, and T/B cells, towards the site of inflammation. These cells progressively infiltrate the deeper layers to the periodontal connective tissue, including the alveolar bone [133,134]. As a result, the stimulation and activation of osteoclasts, coupled with the inhibition of osteoblasts, disrupts the delicate balance between bone resorption and regeneration, ultimately resulting in a decrease in bone volume [135]. The pathogenesis of alveolar bone loss is a complex and multifaceted process, involving a broad array of cellular and molecular interactions. Meanwhile, tissue engineering has advanced to the point where it can offer the potential to restore lost alveolar bone, periodontal ligament, and root cementum. Tissue engineering has opened new avenues for achieving predictable and optimal periodontal tissue regeneration. Understanding the intricacies of the bone remodeling process and the factors that regulate it is critical to developing effective therapies for periodontitis and other bone-related diseases.