Is preexisting inflamed jaw marrow a "hidden" co-morbidity affecting outcomes of COVID-19 infections? - Clinical comparative study.

Introduction: Exceedingly high levels of the chemokine CCL5/RANTES have been found in fatty degenerated osteonecrotic alveolar bone cavities (FDOJ) and aseptic ischemic osteolysis of the jaw (AIOJ) from toothless regions. Because CCL5/RANTES seems to have a prominent role in creating the COVID-19 "cytokine storm", some researchers have used the monoclonal antibody Leronlimab to block the CCR5 on inflammatory cells.Objective: Is preexisting FDOJ/AIOJ jaw marrow pathology a "hidden" co-morbidity affecting some COVID-19 infections? To what extent does the chronic CCL5/RANTES expression from preexisting FDOJ/AIOJ areas contribute to the progression of the acute cytokine storm in COVID-19 patients?Methods: Authors report on reducing the COVID-19 "cytokine storm" by treating infected patients through targeting the chemokine receptor 5 (CCR5) with Leronlimab and interrupting the activation of CCR5 by high CCL5/RANTES signaling, thus dysregulating the inflammatory phase of the viremia. Surgical removal of FDOJ/AIOJ lesions with high CCL5/RANTES from patients with inflammatory diseases may be classified as a co-morbid disease.Results: Both multiplex analysis of 249 FDOJ/AIOJ bone tissue samples as well as serum levels of CCL5/RANTES displayed exceedingly high levels in both specimens.Discussion: By the results the authors hypothesize that chronic CCL5/RANTES induction from FDOJ/AIOJ areas may sensitize CCR5 throughout the immune system, thus, enabling it to amplify its response when confronted with the virus. As conventional intraoral radiography does little to assess the quality of the alveolar bone, ultrasonography units are available to help dentists locate the FDOJ/AIOJ lesions in an office setting.Conclusion: The authors propose a new approach to containment of the COVID-19 cytokine storm by a prophylactic focus for future viral-related pandemics, which may be early surgical clean-up of CCL5/RANTES expression sources in the FDOJ/AIOJ areas, thus diminishing a possible pre-sensitization of CCR5. A more complete dental examination includes trans-alveolar ultrasono-graphy (TAU) for hidden FDOJ/AIOJ lesions.

Osteoimmune Interaction and TH-1/TH-2 Ratio in Jawbone Marrow Defects: An Underestimated Association - Original Research.

Introduction: Osteoimmunology recognizes the relationship between bone cells and immune cells. Chronic osteoimmune dysregulation is present in bone marrow defects of the jaw (BMDJ) as fatty-degenerative osteonecrosis (FDOJ). In comparison to samples from healthy jaw bone, the cytokine analysis of samples of BMDJ/FDOJ from 128 patients showed downregulated TNF-α and IL-6 expression and the singular overexpression of the chemokine RANTES/CCL5. Aim and Objectives: This paper raises the question of whether the osteoimmune defects due to incomplete wound healing in BMDJ/FDOJ in 128 patients are related to dysregulation of the Th1/Th2 ratio and regulatory T cell (T-reg) expression in a control group of 197 BMDJ/FDOJ patients, each presenting with BMDJ/FJOD and one of seven different immune disorders. Material and Methods: In the control group, serum concentrations of the cytokines IFN-y and IL-4 were determined after stimulated cytokine release and displayed as Th1/Th2 ratios. Results: Data show a shift in Th2 in more than 80% (n = 167) of the control cohort of 197 chronically ill patients with concomitant BMDJ/FDOJ. In these 167 subjects, the Th1/Th2 ratio was <6.1 demonstrating impaired immune regulation. Forty-seven subjects or 30% showed not only a shift in Th2 but also excessive T-reg overactivation with levels of >1.900 pg/mL, indicating strongly downregulated immune activity. Discussion: BMDJ/FDOJ is characterized by a lack of Th1 cytokines and an excessive expression of RANTES/CCL5 and IL-1ra and, thus, the inversion of an acute inflammatory cytokine pattern. In contrast, abdominal fat contains a very high proportion of regulatory Th1 cells and produces an inflammatory immune response through the high overexpression of TNF-α and IL-6. The lack of Th1 activation in BMDJ/FDOJ areas inhibits normal wound healing and supports the persistence of BMDJ/FDOJ. Conclusion: The Th1/Th2 ratio requires greater consideration, especially with respect to wound healing following dental surgical interventions, such as jaw surgery, implantation and augmentation, to avoid the emergence of the osteoimmune situation that is characteristic of BMDJ/FDOJ.

Osseointegration and osteoimmunology in implantology: assessment of the immune sustainability of dental implants using advanced sonographic diagnostics: research and case reports.

OBJECTIVE: Bone marrow defects of the jaw (BMDJ) surrounding dental implants, in combination with impaired bone-to-implant contact (BIC), are difficult to detect in X-rays. This study evaluated BMDJ surrounding titanium (Ti-Impl) and ceramic (Cer-Impl) dental implants and incomplete BIC using a new trans-alveolar ultrasonography device (TAU) with numerical scaling for BIC. METHODS: The titanium stimulation test (Ti-Stim) was used to detect immune overactivation in response to titanium. Bone density surrounding implants was measured using TAU. We also validated osteoimmune dysregulation. RESULTS: TAU values showed reduced BIC and decreased osseointegration for Ti-Impl. Moreover, TAU values in the Cer-Impl group were more than twice those in the Ti-Impl cohort. The multiplex analysis of C-C motif chemokine 5 (CCL5, also known as RANTES) expression revealed a 20-fold increase in BMDJ surrounding Ti-Impl. Higher levels of CCL5 inflammation were present in the positive Ti-Stim group. CONCLUSIONS: Our data indicate that Cer-Impl have an osteoimmune advantage over Ti-Impl. The key determinant for osteoimmune sustainability appears to be the absence of inflammation at the implant site. We therefore recommend the use of TAU to assess the implant site prior to implantation.

Comparison of Cytokine RANTES/CCL5 Inflammation in Apical Periodontitis and in Jawbone Cavitations - Retrospective Clinical Study.

Background: Apical periodontitis (AP) is one of the most common endodontic diseases associated with osteo destructive cytokine production. The literature also reports cytokine studies in fatty degenerative osteonecrotic bone marrow defects (BMDJ/FDOJ) independent of AP. Objective: We compare the RANTES/CCL5 (R/C) chemokine production between AP and BMDJ/FDOJ. For both pathologies, the R/C expression was also compared to radiographic diagnosis in 2D-OPG, 3D-CBCT/DVT. Material and Methods: Postoperative samples were collected and divided in three different groups: HB (healthy jawbone) (n=19), APs (n=19), and BMDJ/FDOJ (n=7). The R/C expression was evaluated using multiplex analysis. In addition, two clinical cases from AP and BMDJ/FDOJ groups were randomly selected and radiographic diagnosis in 2D-OPG and 3D-CBCT/DVT was compared to TAU measurements and R/C expression in AP and in BMDJ/FDOJ. Results: BMDJ/FDOJ showed the highest R/C expression (2498.71 pg/mL), followed by AP (841.85 pg/mL) and HB (149.85 pg/mL) (AP vs BMDJ/FDOJ = p=0.01; AP vs HB = p=<0.01; BMDJ/FDOJ vs HB = p=<0.01). In both clinical cases, the radiographic findings depict the AP areas in OPG and CBCT/DVT, in contrast to the BMDJ/FDOJ areas. Conversely, the systemic immunological R/C expressions are threefold and fivefold excessive in both cases. Discussion: AP is recognized as a pathology requiring treatment, while the pathogenesis of BMDJ/FDOJ is controversially discussed in the literature, despite stronger potential systemic immunological effects (breast cancer (case 1) and multiple sclerosis (case 2)). The inadequate radiographic representation of reduced bone density in BMDJ/FDOJ areas could be a reason for this contradiction. Conclusion: The data presented provide the first quantitative analysis of R/C expression in AP and BMDJ/FDOJ. BMDJ/FDOJ showed high R/C expression than AP, besides the diagnostic through radiographs being extremely poor. To cover this imprecision, a radiation-free TAU device is available.

Reduction of Inflammatory RANTES/CCL5 Serum Levels by Surgery in Patients with Bone Marrow Defects of the Jawbone.

Purpose: The presence of bone marrow defects of the jawbone (BMDJ) is associated with increased levels of inflammatory cytokines such as RANTES/CCL5. The purpose of this study was to analyze if BMDJ therapy under real-world conditions reduces RANTES/CCL5 serum levels in BMDJ patients. Patients and Methods: During this retrospective study, 113 BMDJ patients received either no treatment (n = 57), BMDJ surgery (n = 25), tooth extraction (n = 20), or root canal treatment (n = 11). Serum concentrations of RANTES/CCL5, C-reactive protein (CRP), and Tumor Necrosis Factor-α (TNF-α) were assessed before and after treatment (interventional group) and at the beginning and end of the study period (control group). Statistical analyses of the results were performed by the two-sample t-test and Bonferroni post hoc test with ANOVA for multiple comparisons. Results: BMDJ were detected in all patients with 4.42 ± 2.75 BMDJ findings per patient. RANTES/CCL5 levels were significantly reduced by any treatment when compared to no treatment (p < 0.001; effect size d = 0.90). This effect was most pronounced in the BMDJ surgery group (p < 0.001; effect size d = 1.30). In contrast, RANTES/CCL5 serum concentrations further increased in untreated patients. Mean duration between pre- and post-treatment RANTES/CCL5 measurements was 22.86 ± 19.36 weeks, with no correlation with RANTES/CCL5 levels in any interventional group or in the total sample (p = 0.104). Conclusion: BMDJ surgery, tooth extraction, and root canal treatment significantly reduce RANTES/CCL5 serum concentrations in BMDJ patients, with surgery being most beneficial. Further research is required to establish regular RANTES/CCL5 assessments as part of an improved diagnosis, monitoring, and evaluation of therapy success in BMDJ patients.

Linking Dentistry and Chronic Inflammatory Autoimmune Diseases - Can Oral and Jawbone Stressors Affect Systemic Symptoms of Atopic Dermatitis? A Case Report.

Background: This case report demonstrates the value of ultrasound measurements, and immunological and toxicological diagnostics in addition to current x-ray imaging procedures to diagnose hidden oral and maxillofacial infections. Using a clear scheme shows the procedure of the authors' steps. The positive impact on the patient's dermatological clinical picture is shown. Functional regeneration using metal-free ceramic implants and autologous bone augmentation is demonstrated. After a healing period, a postoperative control took place. Question: Are chronic inflammatory and chronic toxic stressors from the oral region affecting the patient's state of health and dermatological symptoms? Patients and Methods: A 52 year old female suffering from neurodermatitis, who had been therapy-resistant for several years, was rehabilitated by oral surgery and prosthetics. Radiological examinations with orthopantomogram (OPG) and three-dimensional imaging (DVT/CBCT) were inconclusive for possible jawbone inflammatory sites. Immunological, toxicological diagnostics and trans-alveolar bone densitometry with ultrasound (TAU), were able to show immunological and toxicological stressors and areas of reduced bone density. Bone densitometry with ultrasound raised the suspicion of silent inflammations in the jawbone with potentially increased cytokine levels. Results: For the patient incompatible materials, teeth with increased toxin exposure and surrounding softened, fatty, ischaemic bone was removed. Histologies and cytokine profiles were obtained. The resulting defects were functionally regenerated using ceramic implants and autologous augmentation. The cytokine profiles showed significantly elevated RANTES/CCL5, confirming the need for surgical intervention. The patient's atopic dermatitis improved significantly in this case. Summary: Individualized immunological and toxicological diagnostics and trans-alveolar bone density bone densitometry with ultrasound (TAU) identified immunological and toxicological stressors as well as reduced bone density with increased cytokine levels. A therapy-resistant neurodermatitis improved significantly after treatment. Conclusion: This case report illustrates the need for patient-specific and individualized examinations that link dentistry more closely with other medical conditions in order to clarify possible interactions.

Focal Bone-Marrow Defects in the Jawbone Determined by Ultrasonography-Validation of New Trans-Alveolar Ultrasound Technique for Measuring Jawbone Density in 210 Participants.

Ultrasound imaging of the jawbone is not currently used in dental medicine to determine bone density. Bone-marrow defects in the human jawbone (BMDJ/FDOJ) are widely discussed in dentistry owing to their role in implant failures and as sources of inflammation in various immune diseases. The use of through-transmission alveolar ultrasonography (TAU) to locate BMDJ/FDOJ was evaluated in this study using a new TAU apparatus (TAU-n). The objective was to determine whether TAU-n readings accurately indicate the clinical parameters to detect BMDJ/FDOJ. Three parameters were compared with TAU-n measurements: 2-D orthopantomogram, Hounsfield units using digital volume tomography and post-operatively measured levels of RANTES/CCL5 expression in BMDJ/FDOJ samples. Based on the available clinical data, Hounsfield units, RANTES/CCL5 expression and TAU-n color codes yielded consistent results with respect to bone mineral density. Thus, ultrasonography with TAU-n is a reliable and efficient diagnostic method to screen for BMDJ/FDOJ in dentistry.

RANTES/CCL5 Signaling from Jawbone Cavitations to Epistemology of Multiple Sclerosis - Research and Case Studies.

BACKGROUND: The role played by signaling pathways in the cell-cell communication associated with multiple sclerosis (MS) progression has become a critical area in research. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also named chemokine C-C motif ligand 5 (CCL5; R/C), is a protein that has been investigated in neuroinflammatory research due to its link to MS development. OBJECTIVE: Research on bone marrow defects in the jawbone (BMDJ), which morphologically presents as fatty-degenerative osteonecrosis of the jawbone (FDOJ), presents overexpression of R/C signaling in affected areas. Here, we try to elucidate the potential link between jawbone-derived R/C and MS. METHODS: Seventeen BMDJ/FDOJ samples extracted from 17 MS patients, as well as samples from 19 healthy controls, were analyzed for R/C expression using bead-based Luminex® analysis. The serum R/C levels from 10 MS patients were examined. Further, bone density, histology, and R/C expression were analyzed in two clinical case studies. RESULTS: High R/C overexpression was found in all BMDJ/FDOJ samples obtained from the MS group. Serum R/C levels were also upregulated in the MS group. R/C serum levels in the MS cohort were higher than in the healthy controls. In contrast, the histology of BMDJ/FDOJ samples showed no inflammatory cells. DISCUSSION: R/C-induced "silent inflammation" in MS is widely discussed in the scientific literature, along with R/C triggering of inflammation in the central nervous system, which might be key in the development of MS. CONCLUSION: The authors suspect that BMDJ/FDOJ may serve as a trigger of MS progression via R/C overexpression. As such, the dental and medical communities should be made aware of BMDJ/FDOJ in cases of MS.

Jawbone Cavitation Expressed RANTES/CCL5: Case Studies Linking Silent Inflammation in the Jawbone with Epistemology of Breast Cancer.

BACKGROUND: The role of signaling pathways as part of the cell-cell communication within cancer progression becomes a crucial area. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also known as the chemokine C-C motif ligand 5 (CCL5) (R/C), is a protein on which cancer research focus due to its link with aggressive cancer development. OBJECTIVE: Research on fatty-degenerative osteonecrosis in jawbone (FDOJ) shows striking overexpression of R/C in these areas. Here we try to elucidate a potential link between jawbone-derived R/C and breast cancer (BC) and compare these findings by immunohistochemical staining. METHODS: Thirty-nine FDOJ samples extracted from 39 BC patients and samples from 19 healthy control were analyzed for R/C expression using bead-based Luminex® analysis. R/C levels from 5 BC patients were measured in serum before and after FDOJ surgery. Bone density, histology, R/C expression, and immunohistochemistry were analysed in 4 clinical case studies. The R/C staining of two FDOJ BC patients is compared with the immunohistochemical staining of BC cell preparations. RESULTS: A high overexpression of R/C was seen in all FDOJ samples. R/C levels in serum were statistically downregulated after FDOJ surgery (p=0.0241). DISCUSSION: R/C induced "silent inflammation" in BC is widely discussed in scientific papers along with R/C triggering of different signaling pathways, which might be a key point in the development of BC. CONCLUSION: Hypothesis that FDOJ may serve as a trigger of BC progression through R/C overexpression was set by the authors, who thus inspire clinicians to make aware of FDOJ throughout the dental and medical community in BC cases.

Undetected Jawbone Marrow Defects as Inflammatory and Degenerative Signaling Pathways: Chemokine RANTES/CCL5 as a Possible Link Between the Jawbone and Systemic Interactions?

BACKGROUND: Cytokines, especially chemokines, are of increasing interest in immunology. This study characterizes the little-known phenomenon of "bone marrow defects of the jawbone" (BMDJ) with known overexpression of the chemokine RANTES/CCL5 (R/C). PURPOSE: Our investigation clarifies why BMDJ and the intensity of local R/C overexpression are challenging to detect, as examined in patients with seven different systemic immunological diseases. Specifically, we investigate whether R/C overexpression is specific to certain disease groups or if it represents a type of signal disruption found in all systemic immunological diseases. PATIENTS AND METHODS: In a total of 301 patients, BMDJ was surgically repaired during clinical practice to reduce "silent inflammation" associated with the presence of jaw-related pathologies. In each case of BMDJ, bone density was measured preoperatively (in Hounsfield units [HU]), while R/C expression was measured postoperatively. Each of the 301 patients suffered from allergies, atypical facial and trigeminal pain, or were diagnosed with neurodegenerative diseases, tumors, rheumatism, chronic fatigue syndrome, or parasympathetic disorders. RESULTS: In all BMDJ cases, strongly negative HU values indicated decreased bone density or osteolysis. Consistently, all cases of BMDJ showed elevated R/C expression. These findings were consistently observed in every disease group. DISCUSSION: BMDJ was confirmed in all patients, as verified by the HU measurements and laboratory results related to R/C expression. The hypothesis that a specific subset of the seven disease groups could be distinguished either based on the increased presence of BMDJ and by the overexpression of R/C could not be confirmed. A brief literature review confirms the importance of R/C in the etiology of each of the seven disease groups. CONCLUSION: In this research, the crucial role played by BMDJ and the chemokine R/C in inflammatory and immune diseases is discussed for seven groups of patients. Each specific immune disease can be influenced or propelled by BMDJ-derived R/C inflammatory signaling pathways.

Chronic Fatigue Syndrome and Bone Marrow Defects of the Jaw - A Case Report on Additional Dental X-Ray Diagnostics with Ultrasound.

PURPOSE: This paper aims to demonstrate the additional benefit of ultrasound in the diagnosis of chronic osteolysis and osteonecrosis (bone marrow defects) of the jaw shown in a clinical case report. PATIENTS AND METHODS: A case of chronic fatigue syndrome (CFS) in a young man presenting the typical, ambiguous symptoms, which were accompanied by headaches and tinnitus. X-ray techniques, namely panoramic radiographs (OPG) and cone beam computed tomography (DVT/CBCT), failed to produce any remarkable findings of bone marrow defects (BMDJ) in the jawbone. However, the measurement of bone density using trans-alveolar ultrasound (TAU) indicated a possible bone marrow defect in the lower left jawbone. RESULTS: Surgery was undertaken at the conspicuous area. Additional to softened, ischemic, fatty tissue, a black area was revealed, which was surprisingly subsequently identified as aspergillosis by histopathological analysis. In addition, the excessive local RANTES/CCL5 expression found in the affected area confirmed the necessity for surgical debridement and additional findings of TAU. CONCLUSION: In contrast to radiography, complementary TAU imaging of the BMDJ revealed chronic inflammatory signaling RANTES/CCL5 pathways and fungal colonization. This case report supports the need for additional diagnostic techniques beyond radiographic modalities, which can help to elucidate the diagnostic composition and knowledge of the bone manifestations of systemic diseases.

Osteonecrosis of the Jaw Beyond Bisphosphonates: Are There Any Unknown Local Risk Factors?

INTRODUCTION: Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is a complication of intravenous (IV) BP therapy. BP therapy locally affects the dentoalveolar area, while systemic effects are associated with parenteral/IV BP use. Despite numerous publications, the pathogenesis of BRONJ is not fully understood, as only some patients receiving IV BPs develop BRONJ. PURPOSE: Can impaired bone remodeling (found in aseptic-ischemic osteonecrosis of the jaw [AIOJ], bone marrow defects [BMD], or fatty-degenerative osteonecrosis of the jaw [FDOJ]) represent a risk factor for BRONJ formation? PATIENTS AND METHODS: A literature search clarified the relationship between AIOJ, BMD, FDOJ, and BRONJ, in which common characteristics related to signal cascades, pathohistology, and diagnostics are explored and compared. A case description examining non-exposed BRONJ is presented. DISCUSSION: Non-exposed BRONJ variants may represent one stage in undetected BMD development, and progression to BRONJ results from BPs. CONCLUSION: Unresolved wound healing at extraction sites, where wisdom teeth have been removed for example, may contribute to the pathogenesis of BRONJ. With IV BP administration, persisting AIOJ/BMD/FDOJ areas may be behind BRONJ development. Therapeutic recommendations include IV BP administration following AIOJ/BMD/FDOJ diagnosis and surgical removal of ischemic areas. BPs should not be regarded as the only cause of osteonecrosis.

Mitochondrial Function and Root-Filled Teeth - Detrimental and Unknown Interfaces in Systemic Immune Diseases.

BACKGROUND: Mitochondriopathy has recently been linked to several immune system diseases. Historically, there have been many conversations regarding the possible toxic effects of root-filled teeth (RFT), although discussions about the possible decreases in adenosine triphosphate (ATP) activity on the mitochondrial membrane, as caused by dental toxins, are rare. In fact, only a few methods currently exist to assess toxin release in teeth. OBJECTIVE: An experimental clinical study design is used to investigate the extent to which RFT release toxins in a solution created specifically following extraction (Tox-sol). Our laboratory is investigating the extent to which these Tox-sols reduce ATP activity in patients. PATIENTS AND METHODS: RFTs were identified and extracted to assess their local toxin release using a semi-quantitative volatile sulfur compound indicator (VSCI). These RFTs are placed in an aqueous solution at room temperature for 24 hours and subsequently removed. The resulting solution (Tox-sol) is diluted to 1:100; peripheral blood mononuclear cells (PBMCs) obtained from patients were added to the solution in the laboratory. The remaining ATP activity was measured on the mitochondrial membrane and was compared with the baseline ATP activity of each patient. RESULTS: The total population (n=30) showed a ~10% reduction in ATP activity following 24 hours of exposure to the Tox-sol. Three groups emerged with greatly reduced (n=16), neutral (n=10), and increased (n=4) ATP activity. In four different disease groups (rheumatism, neurological disorders, allergies, and tumors), a non-disease specific inhibition of ATP activity was observed. DISCUSSION: The study design was limited, as patients were exposed to the Tox-sol and PBMC fraction for only 24 hours. The actual exposure time in a patient's mouth can continue for years and the actual levels can increase over time. Disease-specific effects of Tox-sol were not found. CONCLUSION: Within the short exposure time of 24 hours, and at a dilution of 1:100, the Tox-sol caused a median decrease in ATP activity of ~15% in 50% of test subjects. A practical VSCI reliably showed the effects of toxic sulfur compounds on the RFT. The toxic degradation products of biogenic amines from RFT can thus serve as possible contributing factors in the development of mitochondriopathies.

Ultrasound Sonography to Detect Focal Osteoporotic Jawbone Marrow Defects Clinical Comparative Study with Corresponding Hounsfield Units and RANTES/CCL5 Expression.

INTRODUCTION: The presently used impulse echo ultrasound examination is not suitable to provide relevant and reliable information about the jawbone, because ultrasound (US) almost completely reflects from the hard cortical jawbone. At the same time, "focal osteoporotic bone marrow defects" (BoneMarrowDefects = BMD) in jawbone are the subject of scientific presentations and discussions. PURPOSE: Can a newly developed trans-alveolar ultrasonic sonography (TAU-n) device locate and ascertain BMD? PATIENTS AND METHODS: TAU-n consists of a two-part handpiece with an extraoral ultrasound transmitter and an intraoral ultrasound receiver. The TAU-n computer display shows the different jawbone densities with corresponding colour coding. The changes in jawbone density are also displayed numerically. The validation of TAU-n readings: A usual orthopantomogram (2D-OPG) on its own is not suitable for unequivocally determining jawbone density and has to be excluded from this validation. For validation, a 3D-digital volume tomogram@/cone beam computer tomogram (DVT@/CBCT) with the capacity to measure Hounsfield units (HU) and a TAU-n are used to determine the presence of preoperative BMD in 82 patient cases. Postoperatively, histology samples and multiplex analysis of RANTES@/CCL5 (R@/C) expression derived from surgically cleaned BMD areas are evaluated. RESULTS: In all 82 bone samples, DVT-HU, TAU-n values and R/C expressions show the presence of BMD with chronic inflammatory character. However, five histology samples showed no evidence of BMD. All four evaluation criteria (DVT-HU, TAU-n, R/C, histology) confirm the presence of BMD in each of the 82 samples. CONCLUSION: The TAU-n method almost completely matches the diagnostic reliability of the other methods. The newly developed TAU-n scanner is a reliable and radiation-free option to detect BMD.

Immunohistological staining of unknown chemokine RANTES/CCL5 expression in jawbone marrow defects-osteoimmunology and disruption of bone remodeling in clinical case studies targeting on predictive preventive personalized medicine.

BACKGROUND: Fatty degenerative osteonecrosis in the medullary spaces of the jawbone (FDOJ) may be identified as a lesser known source of RANTES/CCL5 (R/C) overexpression. The chemokine R/C also interferes with bone metabolism leading to osteolysis in areas affected by FDOJ. Many dental surgeries require functioning repair mechanisms and these may be disrupted by R/C overexpression. OBJECTIVE: To clarify the way in which R/C expression from adipocytes in FDOJ causes a disturbance in osteogenesis and impacts on medullary stem cells by investigating the detection of R/C expression with immunochemical staining. MATERIALS AND METHODS: We examined the tissue samples of 449 patients with FDOJ to assess the level of the chemokine R/C using bead-based Luminex® analysis. In six clinical case studies of FDOJ, we compared bone density, histological findings, R/C expression, and immunohistochemical staining. RESULTS: R/C is overexpressed by up to 30-fold in the 449 FDOJ cases when compared with healthy jawbone samples. The comparison of the six clinical cases consistently shows greatly reduced bone density, (i.e., osteolysis), but varies in terms of the level of agreement across the other three parameters. DISCUSSION: R/C from FDOJ sources may be implicated in several immune responses and considered a key pathogenetic pathway for increased adipogenesis rather than desirable osteogenesis. Adipocytes pathogenetically act via R/C expression in local FDOJ and systemically on the immune system. CONCLUSION: R/C may be regarded as an important trigger for possible pathological developments in the fate of hematopoietic stem cells. FDOJ is not a rigidly uniform process but reflects changing stages of development. The absence of correlating findings should not be interpreted as a misdiagnosis. It seems appropriate to direct further research in the field of "maxillo-mandibular osteoimmunology" focusing on R/C overexpression in FDOJ areas. This may contribute to the development of personalized strategies in preventive medicine.

Osteoimmunology of tumor necrosis factor-alpha, IL-6, and RANTES/CCL5: a review of known and poorly understood inflammatory patterns in osteonecrosis.

BACKGROUND: The immune and bone systems are closely linked via cytokine cross-talk. This interdisciplinary field of research is referred to as osteoimmunology and pertains to inflammatory and osteoarticular diseases that feature the primary expression of tumor necrosis factor-alpha (TNF-α) and IL-6. OBJECTIVE: Are there bone resorptive processes wherein chronic inflammatory conditions are not linked to TNF-α and IL-6 expression, but rather to the expression of other cytokines? MATERIALS AND METHODS: A comprehensive literature search was performed in PubMed Central. DISCUSSION: Although all diseases with cytokines involved in bone resorption (TNF-α and IL-6) are at the forefront of destructive inflammatory processes, there is one exception in the literature: fatty oxide osteoporosis/osteolysis in the jawbone (FDOJ), which is associated with significant bone softening. However, it should be noted that TNF-α and IL-6 fall below the levels found in a healthy jawbone in this condition. Another conspicuous finding is that there is a nearly 35-fold overexpression of the chemokine RANTES/CCL5 (R/C) in all FDOJ cases studied thus far in the literature. CONCLUSION: FDOJ appears to represent a unique cytokine and inflammatory pattern from osteolysis in the body. R/C can be defined as the dominant carrier of a "maxillomandibular osteoimmunology".

Titanium implants and silent inflammation in jawbone-a critical interplay of dissolved titanium particles and cytokines TNF-α and RANTES/CCL5 on overall health?

BACKGROUND AND INTRODUCTION: It is a well-known fact that titanium particles deriving from dental titanium implants (DTI) dissolve into the surrounding bone. Although titanium (TI) is regarded as a compatible implant material, increasing concern is coming up that the dissolved titanium particles induce inflammatory reactions around the implant. Specifically, the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is expressed in the adjacent bone. The transition from TNF-α-induced local inflammation following insertion of DTI surgery to a chronic stage of "silent inflammation" could be a neglected cause of unexplained medical conditions. MATERIAL AND METHODS: The signaling pathways involved in the induction of cytokine release were analyzed by multiplex analysis. We examined samples of jawbone (JB) for seven cytokines in two groups: specimens from 14 patients were analyzed in areas of DTI for particle-mediated release of cytokines. Each of the adjacent to DTI tissue samples showed clinically fatty degenerated and osteonecrotic medullary changes in the JB (FDOJ). Specimens from 19 patients were of healthy JB. In five cases, we measured the concentration of dissolved Ti particles by spectrometry. RESULTS: All DTI-FDOJ samples showed RANTES/CCL5 (R/C) as the only extremely overexpressed cytokine. DTI-FDOJ cohort showed a 30-fold mean overexpression of R/C as compared with a control cohort of 19 healthy JB samples. Concentration of dissolved Ti particles in DTI-FDOJ was 30-fold higher than an estimated maximum of 1.000 µg/kg. DISCUSSION: As R/C is discussed in the literature as a possible contributor to inflammatory diseases, the here-presented research examines the question of whether common DTI may provoke the development of chronic inflammation in the jawbone in an impaired state of healing. Such changes in areas of the JB may lead to hyperactivated signaling pathways of TNF-α induced R/C overexpression, and result in unrecognized sources of silent inflammation. This may contribute to disease patterns like rheumatic arthritis, multiple sclerosis, and other systemic-inflammatory diseases, which is widely discussed in scientific papers. CONCLUSION: From a systemic perspective, we recommend that more attention be paid to the cytokine cross-talk that is provoked by dissolved Ti particles from DTI in medicine and dentistry. This may contribute to further development of personalized strategies in preventive medicine.

The vitamin D receptor and the etiology of RANTES/CCL-expressive fatty-degenerative osteolysis of the jawbone: an interface between osteoimmunology and bone metabolism.

BACKGROUND: Recent research on vitamin D indicates that our current understanding of the factors leading to chronic inflammation should be revised. One of the key mechanisms by which microbial immunosuppression occurs is the suppression of one of the most common endogenous cell nucleus receptors: the vitamin D receptor (VDR). Autoimmune diseases may be correlated with VDR deactivation (VDR-deac) which occurs when the receptor is no longer able to transcribe antimicrobial agents. Excess 1,25-dihydroxyvitamin D (1,25D) is not converted to 25-hydroxyvitamin D (25D); thus, high 1,25D levels may be accompanied by low 25D values. PATIENTS AND METHODS: Since 1,25D promotes osteoclast activity and may thereby cause osteoporosis, fatty-degenerative osteolysis of the jaw (FDOJ), as described by our team, may also be associated with VDR-deac. In 43 patients, vitamin D conversion, immune system function and the quality of bone resorption and formation in the jawbone were related factors that may enhance chronic inflammatory processes. Here, we examine the relationship between immunology and bone metabolism among 43 FDOJ patients and those with immune system diseases (ISDs). RESULTS: We provide a link between FDOJ, RANTES/CCL5 overexpression and VDR-deac. CONCLUSION: The clinical data demonstrate the interaction between VDR-deac and proinflammatory RANTES/CCL5 overexpression in FDOJ patients.