The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry.

Purpose of the Review: Aging clearly impacts a wide array of systems, in particular the breadth of the immune system leading to immunosenescence, altered immunoactivation, and coincident inflammaging processes. The net result of these changes leads to increased susceptibility to infections, increased neoplastic occurrences, and elevated frequency of autoimmune diseases with aging. However, as the bacteria in the oral microbiome that contribute to the chronic infection of periodontitis is acquired earlier in life, the characteristics of the innate and adaptive immune systems to regulate these members of the autochthonous microbiota across the lifespan remains ill defined. Recent Findings: Clear data demonstrate that both cells and molecules of the innate and adaptive immune response are adversely impacted by aging, including in the oral cavity, yielding a reasonable tenet that the increased periodontitis noted in aging populations is reflective of the age-associated immune dysregulation. Additionally, this facet of host-microbe interactions and disease needs to accommodate the population variation in disease onset and progression, which may also reflect an accumulation of environmental stressors and/or decreased protective nutrients that could function at the gene level (ie. epigenetic) or translational level for production and secretion of immune system molecules. Summary: Finally, the majority of studies of aging and periodontitis have emphasized the increased prevalence/severity of disease with aging, all based upon chronological age. However, evolving areas of study focusing on “biological aging” to help account for population variation in disease expression, may suggest that chronic periodontitis represents a co-morbidity that contributes to “gerovulnerability” within the population.

Microgravity (µXg) leads to a 10-15% loss of bone mass in astronauts during space flight. Osteoclast (OCL) is the multinucleated bone-resorbing cell. In this study, we used the NASA developed ground-based rotating wall vessel bioreactor (RWV), rotary cell culture system (RCCS) to simulate µXg conditions and demonstrated a significant increase (2-fold) in osteoclastogenesis compared to normal gravity control (Xg). Gene expression profiling of RAW 264.7 OCL progenitor cells in modelled µXg by Agilent microarray analysis revealed significantly increased expression of critical molecules such as cytokines/growth factors, proteases and signalling proteins, which play an important role in enhanced OCL differentiation/function. Transcription factors such as c-Jun, MITF and CREB implicated in OCL differentiation are upregulated; however no significant change in the levels of NFATc1 expression in preosteoclast cells subjected to modelled µXg. We also identified high-level expression of calcium-binding protein, S100A8 (calcium-binding protein molecule A8/calgranulin A) in preosteoclast cells under µXg. Furthermore, modelled µXg stimulated RAW 264.7 cells showed elevated cytosolic calcium (Ca(2+)) levels/oscillations compared to Xg cells. siRNA knock-down of S100A8 expression in RAW 264.7 cells resulted in a significant decrease in modelled µXg stimulated OCL differentiation. We also identified elevated levels of phospho-CREB in preosteoclast cells subjected to modelled µXg compared to Xg. Thus, modelled µXg regulated gene expression profiling in preosteoclast cells provide new insights into molecular mechanisms and therapeutic targets of enhanced OCL differentiation/activation to prevent bone loss and fracture risk in astronauts during space flight missions.

Background: Although loss of the Ostm1 gene leads to the most severe form of osteopetrosis, Ostm1 is expressed in other tissues, including the CNS. Results: Independently of hematopoietic lineages, loss of Ostm1 results in acute neurodegeneration with enhanced autophagy. Conclusion: We present evidence for an Ostm1 cell-autonomous role in neurons. Significance: This study shows a novel molecular pathogenic mechanism for neurodegeneration-related diseases.

Aim Cellular and molecular immunoinflammatory changes in gingival tissues drive alveolar bone loss in periodontitis. Since aging is a risk factor for periodontitis, we sought to identify age-related gingival transcriptome changes associated with bone metabolism in both healthy and in naturally-occurring periodontitis. Materials and Methods Adult (12–16 years) and aged (18–23 years) non-human primates (M. mulatta) (n=24) were grouped into healthy and periodontitis. Gingival tissue samples were obtained and subjected to microarray analysis using the Gene Chip Macaque Genome Array. Gene expression profiles involved in osteoclast/osteoblast proliferation, adhesion, and function were evaluated and compared across and between the age groups. QPCR was also performed on selected genes to validate microarray data. Results Healthy aged tissues showed a gene profile expression that suggest enhancement of osteoclastic adhesion, proliferation/survival and function (SPP1, TLR4, MMP8, and TFEC) and impaired osteoblastic activity (SMEK3P and SMAD5). The gingival transcriptome in both adult and aged animals with naturally-occurring periodontitis (FOS, IL6, TLR4, MMP9, MMP10 and SPP1 genes) was consistent with a local inflammatory response driving towards bone/connective tissue destruction. Conclusion A pro-osteoclastogenic gingival transcriptome is associated with periodontitis irrespective of age; however; a greater bone-destructive molecular environment is associated with aging in healthy tissues.

Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal tissue gene expression profiles focusing on cells/genes critical for the development of humoral adaptive immune responses. Patterns of B cell and plasmacyte genes were altered in aging healthy gingival tissues. Substantial increases in a large number of genes reflecting antigen-dependent activation, B cell activation, B cell proliferation, and B cell differentiation/maturation were observed in periodontitis in adults and aged animals. Finally, evaluation of the relationship of these gene expression patterns with those of various tissue destructive molecules (MMP2, MMP9, CTSK, TNFα, and RANKL) showed a greater frequency of positive correlations in healthy tissues versus periodontitis tissues, with only MMP9 correlations similar between the two tissue types. These results are consistent with B cell response activities in healthy tissues potentially contributing to muting the effects of the tissue destructive biomolecules, whereas with periodontitis this relationship is adversely affected and enabling a progression of tissue destructive events.

In osteoclasts, Src controls podosome organization and bone degradation, which leads to an osteopetrotic phenotype in src(-/-) mice. Since this phenotype was even more severe in src(-/-)hck(-/-) mice, we examined the individual contribution of Hck in bone homeostasis. Compared to wt mice, hck(-/-) mice exhibited an osteopetrotic phenotype characterized by an increased density of trabecular bone and decreased bone degradation, although osteoclastogenesis was not impaired. Podosome organization and matrix degradation were found to be defective in hck(-/-) osteoclast precursors (preosteoclast) but were normal in mature hck(-/-) osteoclasts, probably through compensation by Src, which was specifically overexpressed in mature osteoclasts. As a consequence of podosome defects, the 3-dimensional migration of hck(-/-) preosteoclasts was strongly affected in vitro. In vivo, this translated by altered bone homing of preosteoclasts in hck(-/-) mice: in metatarsals of 1-wk-old mice, when bone formation strongly depends on the recruitment of these cells, reduced numbers of osteoclasts and abnormal developing trabecular bone were observed. This phenotype was still detectable in adults. In summmary, Hck is one of the very few effectors of preosteoclast recruitment described to date and thereby plays a critical role in bone remodeling.

Oral squamous cell carcinomas (OSCC) are malignant tumors with a potent activity of local bone invasion; however, the molecular mechanisms of tumor osteolysis are unclear. In this study, we identified high level expression of chemokine ligand, CXCL13 and RANK ligand (RANKL) in OSCC cells (SCC1, SCC12 and SCC14a). OSCC cell-conditioned media (20%) induced osteoclast differentiation which was inhibited by OPG in peripheral blood monocyte cultures indicating that OSCC cells produce soluble RANKL. Recombinant hCXCL13 (10 ng/ml) significantly enhanced RANKL-stimulated osteoclast differentiation in these cultures. Trans-well migration assay identified that CXCL13 induces chemotaxis of peripheral blood monocytes in vitro which was inhibited by addition of anti-CXCR5 receptor antibody. Zymogram analysis of conditioned media from OSCC cells revealed matrix metalloproteinase-9 (MMP-9) activity. Interestingly, CXCL13 treatment to OSCC cells induced CXCR5 and MMP-9 expression suggesting an autocrine regulatory function in OSCC cells. To examine the OSCC tumor cell bone invasion/ osteolysis, we established an in vivo model for OSCC by subcutaneous injection of OSCC cells onto the surface of calvaria in NCr-nu/nu athymic mice, which developed tumors in 4-5 weeks. lCT analysis revealed numerous osteolytic lesions in calvaria from OSCC tumor-bearing mice. Histochemical staining of calvarial sections from these mice revealed a significant increase in the numbers of TRAP-positive osteoclasts at the tumor-bone interface. Immunohistochemical analysis confirmed CXCL13 and MMP-9 expression in tumor cells. Thus, our data implicate a functional role for CXCL13 in bone invasion and may be a potential therapeutic target to prevent osteolysis associated with OSCC tumors in vivo.Head and neck squamous cell carcinoma (HNSCC) are the most common malignant neoplasms, with a prevalence estimated to be greater than 40,000 cases annually in the US. Oral squamous cell carcinoma (OSCC), which contributes to 40% of all HNSCC is associated with mucosal surfaces of the oral cavity and oropharynx. 1 The etiology of OSCC involves both a genetic predisposition and exposure to environmental carcinogens such as tobacco, alcohol, chronic inflammation and viral infection. 2 Curcumin has been shown to suppress HNSCC growth both in vitro and in vivo, 3 and Fas-mediated apoptosis in HNSCC is a proven and efficient therapeutic approach in a xenograft animal model. 4 Furthermore, tamoxifen inhibition of OSCC cell growth in vitro 5 and a role for human longevity assurance gene 1 (LASS1) and C 18 -ceramide in chemotherapy induced cell death in HNSCC have been reported. 6 Malignant HNSCC tumors are known to have a potent activity of local bone invasion; however, the molecular mechanisms of tumor-associated osteolysis are unclear.The osteoclast is hematopoietic in origin and is the boneresorbing cell derived from monocyte/macrophage lineage. Tumor necrosis factor (TNF) family member, RANK ligand (RANKL), which is expressed on marrow stromal/osteoblast cells in respo...