MMP-12 and Periodontitis: Unraveling the Molecular Pathways of Periodontal Tissue Destruction.

Periodontal disease is a common disorder affecting a wide range of people and has a high prevalence globally. Periodontitis comprises a series of inflammatory conditions affecting periodontal support tissue, which could ultimately lead to tooth loss and reduce life quality and add to the financial burden of society. Matrix metalloproteinase-12 (MMP-12) is an elastase that is produced mostly by macrophages and could degrade a wide spectrum of extracellular matrix (ECM) and also contribute to several systematic pathological conditions. Recently, researchers have reported higher expression of MMP-12 in chronic periodontitis patients. However, there are few reports on the role of MMP-12 in periodontitis pathogenicity, and the interaction between MMP-12, periodontal pathogens, and periodontal tissues remains unclear. In this review, we introduce the potentially unique role of MMP-12 in the context of periodontal inflammation earlier, summarize the possible effects of MMP-12 on the pathological process of periodontitis and the interaction of host response under the challenge of various inflammatory factors, and provide possible diagnostic and therapeutic strategies targeting MMP-12 for the management of periodontitis. Future research and policies should focus on and implement effective chairside testing methods to reduce the prevalence of periodontal diseases.

Macrophage-derived amphiregulin promoted the osteogenic differentiation of chondrocytes through EGFR/Yap axis and TGF-ß activation.

Endochondral ossification represents a crucial biological process in skeletal development and bone defect repair. Macrophages, recognized as key players in the immune system, are now acknowledged for their substantial role in promoting endochondral ossification within cartilage. Concurrently, the epidermal growth factor receptor (EGFR) ligand amphiregulin (Areg) has been documented for its contributory role in restoring bone tissue homeostasis post-injury. However, the mechanism by which macrophage-secreted Areg facilitates bone repair remains elusive. In this study, the induction of macrophage depletion through in vivo administration of clodronate liposomes was employed in a standard open tibial fracture mouse model to assess bone healing using micro-computed tomography (micro-CT) analysis, histomorphology, and ELISA serum evaluations. The investigation revealed sustained expression of Areg during the fracture healing period in wild-type mice. Macrophage depletion significantly reduced the number of macrophages on the local bone surface and vital organs. This reduction led to diminished Areg secretion, decreased collagen production, and delayed fracture healing. However, histological and micro-CT assessments at 7 and 21 days post-local Areg treatment exhibited a marked improvement of bone healing compared to the vehicle control. In vitro studies demonstrated an increase of Areg secretion by the Raw264.7 cells upon ATP stimulation. Indirect co-culture of Raw264.7 and ATDC5 cells indicated that Areg overexpression enhanced the osteogenic potential of chondrocytes, and vice versa. This osteogenic promotion was attributed to Areg's activation of the membrane receptor EGFR in the ATDC5 cell line, the enhanced phosphorylation of transcription factor Yap, and the facilitation of the expression of bioactive TGF-ß by chondrocytes. Collectively, this research elucidates the direct mechanistic effects of macrophage-secreted Areg in promoting bone homeostasis following bone injury.

Neutrophils inhibit bone formation by directly contacting osteoblasts and suppressing osteogenic differentiation.

Neutrophils have been extensively studied for their critical roles in supporting immune defense mechanisms, initiating bone regeneration, and promoting angiogenesis. Nonetheless, the influence of neutrophils on physiological conditions, particularly in the context of bone homeostasis, remains incompletely understood. In this study, we examined the effects of non-inflammatory neutrophils on bone physiology by depleting Ly6G+ neutrophils and inducing neutropenia through myelosuppression. Our results demonstrated a notable increase in bone mass and a decrease in the bone marrow cavity upon depletion of mature neutrophils. This effect was attributed to the direct interaction between neutrophils and osteoblasts, independent of reduced secretion of typical inflammatory cytokines or diminished osteoclast differentiation. This observation suggests a non-inflammatory function of neutrophils within the endosteal microenvironment, where they regulate osteogenic differentiation to preserve optimal bone mass, shape healthy three-dimensional bone trabecular structures, and create ample space for hematopoietic niche development.

Vaccines: Do they have a role in orthopedic trauma?

Although vaccines have been hailed as one of the greatest advances in medicine based on their unparalleled cost-effectiveness in eradicating life-threatening infectious diseases, their role in orthopedic trauma-related infections is unclear. This is largely because vaccines are primarily made against pathogens that cause communicable diseases rather than opportunistic infections secondary to trauma, and most successful vaccines are against viruses rather than biofilm forming bacteria. Nonetheless, the tremendous costs to patients and healthcare systems warrant orthopedic trauma vaccine research, which has been a focal topic in recent international consensus meetings on musculoskeletal infection. This subject was also covered at the 2023 Osteosynthesis and Trauma Care Foundation (OTCF) meeting in Rome, Italy, and the purpose of this supplement article is to (1) highlight the osteoimmunology, animal models, translational research and clinical pilots that were discussed, (2) the proposed future directions that could lead to diagnostics and prognostics that are critically needed for evidence-based decision making, and (3) vaccines and passive-immunization strategies that could potentially be utilized to treat patients with orthopedic infections.

Spatiotemporal Analysis of Mesenchymal Stem Cells Fate Determination by Inflammatory Niche Following Soft Tissue Injury at a Single-Cell Level.

Heterotopic ossification (HO), often arising in response to traumatic challenges, results from the aberrant osteochondral differentiation of mesenchymal stem cells (MSCs). Nevertheless, the impact of trauma-induced inflammatory exposure on MSC fate determination remains ambiguous. In this study, the cellular diversity within inflammatory lesions is elucidated, comprising MSCs and several innate and adaptive immune cells. It is observed that quiescent MSCs transition into cycling MSCs, subsequently giving rise to chondrogenic (cMSC) and/or osteogenic (oMSC) lineages within the inflammatory microenvironment following muscle or tendon injuries, as revealed through single-cell RNA sequencing (scRNA-seq), spatial transcriptome and lineage tracing analysis. Moreover, these investigations demonstrate that neutrophils and natural killer (NK) cells enhance transition of quiescent MSCs into cycling MSCs, which is also controlled by M1 macrophages, a subpopulation of macrophages can also stimulate cMSC and oMSC production from cycling MSCs. Additionally, M2 macrophages, CD4+ and CD8+ T lymphocytes are found to promote chondrogenesis. Further analysis demonstrates that immune cells promotes the activation of signaling transducers and activators of transcription (STAT) pathway and phosphoinositide 3 (PI3K)/protein kinase B (AKT) pathway in MSC proliferation and osteochondral progenitors' production, respectively. These findings highlight the dynamics of MSC fate within the inflammatory lesion and unveil the molecular landscape of osteoimmunological interactions, which holds promise for advancing HO treatment.

The balance between helper T 17 and regulatory T cells in osteoimmunology and relevant research progress on bone tissue engineering.

BACKGROUND: Bone regeneration is a well-regulated dynamic process, of which the prominent role of the immune system on bone homeostasis is more and more revealed by recent research. Before fully activation of the bone remodeling cells, the immune system needs to clean up the microenvironment in facilitating the bone repair initiation. Furthermore, this microenvironment must be maintained properly by various mechanisms over the entire bone regeneration process. OBJECTIVE: This review aims to summarize the role of the T-helper 17/Regulatory T cell (Th17/Treg) balance in bone cell remodeling and discuss the relevant progress in bone tissue engineering. RESULTS: The role of the immune response in the early stages of bone regeneration is crucial, especially the impact of the Th17/Treg balance on osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts activity. By virtue of these knowledge advancements, innovative approaches in bone tissue engineering, such as nano-structures, hydrogel, and exosomes, are designed to influence the Th17/Treg balance and thereby augment bone repair and regeneration. CONCLUSION: Targeting the Th17/Treg balance is a promising innovative strategy for developing new treatments to enhance bone regeneration, thus offering potential breakthroughs in bone injury clinics.

Multifunctionally disordered TiO2 nanoneedles prevent periprosthetic infection and enhance osteointegration by killing bacteria and modulating the osteoimmune microenvironment.

Rationale: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are effective interventions for end-stage osteoarthritis; however, periprosthetic infection is a devastating complication of arthroplasty. To safely prevent periprosthetic infection and enhance osteointegration, the surface modification strategy was utilized to kill bacteria, modulate the osteoimmune microenvironment, and improve new bone formation. Methods: We used the hydrothermal method to fabricate a bionic insect wing with the disordered titanium dioxide nanoneedle (TNN) coating. The mussel-inspired poly-dopamine (PDA) and antibacterial silver nanoparticles (AgNPs) were coated on TNN, named AgNPs-PDA@TNN, to improve the biocompatibility and long-lasting bactericidal capacity. The physicochemical properties of the engineered specimen were evaluated with SEM, AFM, XPS spectrum, and water contact assay. The biocompatibility, bactericidal ability, and the effects on macrophages and osteogenic differentiation were assessed with RT-qPCR, Western blotting, live/dead staining, immunofluorescent staining, etc. Results: The AgNPs-PDA@TNN were biocompatible with macrophages and exhibited immunomodulatory ability to promote M2 macrophage polarization. In addition, AgNPs-PDA@TNN ameliorated the cytotoxicity caused by AgNPs, promoted cell spreading, and increased osteogenesis and matrix deposition of BMSCs. Furthermore, AgNPs-PDA@TNN exhibited bactericidal ability against E. coli and S. aureus by the bionic nanostructure and coated AgNPs. Various imaging analyses indicated the enhanced bactericidal ability and improved new bone formation by AgNPs-PDA@TNN in vivo. H&E, Gram, and Masson staining, verified the improved bone formation, less inflammation, infection, and fibrosis encapsulation. The immunofluorescence staining confirmed the immunomodulatory ability of AgNPs-PDA@TNN in vivo. Conclusion: The bionic insect wing AgNPs-PDA@TNN coating exhibited bactericidal property, immunomodulatory ability, and enhanced osteointegration. Thus, this multidimensional bionic implant surface holds promise as a novel strategy to prevent periprosthetic infection.

Genetic Variants in RANK and OPG Could Influence Disease Severity and Bone Remodeling in Patients with Early Arthritis.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

Mechanochemically Reprogrammed Tantalum Interfaces Enhance Osseointegration Via Immunomodulation.

Bone and tooth defects can considerably affect the quality of life and health of patients, and orthopedic implants remain the primary method of addressing such defects. However, implant materials cannot coordinate with the immune microenvironment because of their biological inertness, which may lead to implant loosening or failure. Motivated by the microstructure of nacre, we engineered a biomimetic micro/nanoscale topography on a tantalum surface using a straightforward method. This comprised an organized array of tantalum nanotubes arranged in a brick wall structure, with epigallocatechin gallate acting as "mortar." The coating improved the corrosion resistance, biocompatibility, and antioxidant properties. In vitro and in vivo evaluations further confirmed that coatings can create a favorable bone immune microenvironment through the synergistic effects of mechanochemistry and enhance bone integration. This research offers a new viewpoint on the creation of sophisticated functional implants, possessing vast potential for use in the regeneration and repair of bone tissue.

Advances on T cell immunity in bone remodeling and bone regeneration. / Tç»†èƒžå ç–«åœ¨éª¨é‡å»ºå’Œéª¨å†ç”Ÿä¸­çš„ç ”ç©¶è¿›å±•.

Bone remodeling and bone regeneration are essential for preserving skeletal integrity and maintaining mineral homeostasis. T cells, as key members of adaptive immunity, play a pivotal role in bone remodeling and bone regeneration by producing a range of cytokines and growth factors. In the physiological state, T cells are involved in the maintenance of bone homeostasis through interactions with mesenchymal stem cells, osteoblasts, and osteoclasts. In pathological states, T cells participate in the pathological process of different types of osteoporosis through interaction with estrogen, glucocorticoids, and parathyroid hormone. During fracture healing for post-injury repair, T cells play different roles during the inflammatory hematoma phase, the bone callus formation phase and the bone remodeling phase. Targeting T cells thus emerges as a potential strategy for regulating bone homeostasis. This article reviews the research progress on related mechanisms of T cells immunity involved in bone remodeling and bone regeneration, with a view to providing a scientific basis for targeting T cells to regulate bone remodeling and bone regeneration.

Macrophage-to-osteocyte communication: Impact in a 3D in vitro implant-associated infection model.

Macrophages and osteocytes are important regulators of inflammation, osteogenesis and osteoclastogenesis. However, their interactions under adverse conditions, such as biomaterial-associated infection (BAI) are not fully understood. We aimed to elucidate how factors released from macrophages modulate osteocyte responses in an in vitro indirect 3D co-culture model. Human monocyte-derived macrophages were cultured on etched titanium disks and activated with either IL-4 cytokine (anti-inflammatory M2 phenotype) or Staphylococcus aureus secreted virulence factors to simulate BAI (pro-inflammatory M1 phenotype). Primary osteocytes in collagen gels were then stimulated with conditioned media (CM) from these macrophages. The osteocyte response was analyzed by gene expression, protein secretion, and immunostaining. M1 phenotype macrophages were confirmed by IL-1ß and TNF-α secretion, and M2 macrophages by ARG-1 and MRC-1.Osteocytes receiving M1 CM revealed bone inhibitory effects, denoted by reduced secretion of bone formation osteocalcin (BGLAP) and increased secretion of the bone inhibitory sclerostin (SOST). These osteocytes also downregulated the pro-mineralization gene PHEX and upregulated the anti-mineralization gene MEPE. Additionally, exhibited pro-osteoclastic potential by upregulating pro-osteoclastic gene RANKL expression. Nonetheless, M1-stimulated osteocytes expressed a higher level of the potent pro-osteogenic factor BMP-2 in parallel with the downregulation of the bone inhibitor genes DKK1 and SOST, suggesting a compensatory feedback mechanisms. Conversely, M2-stimulated osteocytes mainly upregulated anti-osteoclastic gene OPG expression, suggesting an anti-catabolic effect. Altogether, our findings demonstrate a strong communication between M1 macrophages and osteocytes under M1 (BAI)-simulated conditions, suggesting that the BAI adverse effects on osteoblastic and osteoclastic processes in vitro are partly mediated via this communication. STATEMENT OF SIGNIFICANCE: Biomaterial-associated infections are major challenges and the underlying mechanisms in the cellular interactions are missing, especially among the major cells from the inflammatory side (macrophages as the key cell in bacterial clearance) and the regenerative side (osteocyte as main regulator of bone). We evaluated the effect of macrophage polarization driven by the stimulation with bacterial virulence factors on the osteocyte function using an indirect co-culture model, hence mimicking the scenario of a biomaterial-associated infection. The results suggest that at least part of the adverse effects of biomaterial associated infection on osteoblastic and osteoclastic processes in vitro are mediated via macrophage-to-osteocyte communication.

Macrophages modulate mesenchymal stem cell function via tumor necrosis factor alpha in tooth extraction model.

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction (n = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80+M1, CD206+M2 (anti-inflammatory macrophages), PDGFRα+MSC, and TNF-α+ cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm3 vs 0.02 mm3, p<.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p<.0001). Clodronate group showed significant reduction in mean number of CD80+, TNF-α+, PDGFRα+, and CD80+TNF-α+ cells on day 5 (306.5 vs 558.8, p<.0001; 280.5 vs 543.8, p<.0001; 365.0 vs 633.0, p<.0001, 29.0 vs 42.5, p<.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p=.0004; 479.3 vs 384.5, p=.0008; 593.0 vs 473.0, p=.0010, 41.0 vs 32.5, p=.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e, Gbp6, and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity.

Causal relationship between circulating levels of cytokines and bone mineral density: A mendelian randomization study.

BACKGROUND: Numerous studies have shown that various cytokines are important factors affecting bone mineral density (BMD), but the causality between the two remains uncertain. METHODS: Genetic variants associated with 41 circulating cytokines from a genome-wide association study (GWAS) in 8,293 Finns were used as instrumental variables (IVs) for a two-sample Mendelian randomization (MR) analysis. Inverse variance weighting (IVW) was employed as the primary method to investigate whether the 41 cytokines were causally associated with BMD at five different sites [total body bone mineral density (TB-BMD), heel bone mineral density (HE-BMD), forearm bone mineral density (FA-BMD), femoral neck bone mineral density (FN-BMD), and lumbar spine bone mineral density (LS-BMD)]. Weighted median and MR-Egger were chosen to further confirm the robustness of the results. We performed MR pleiotropy residual sum and outlier test (MR-PRESSO), MR-Egger regression, and Cochran's Q test to detect pleiotropy and sensitivity testing. RESULTS: After Bonferroni correction, two circulating cytokines had a strong causality with BMD at corresponding sites. Genetically predicted circulating hepatocyte growth factor (HGF) levels and HE-BMD were negatively correlated [ß (95 % CI) -0.035(-0.055, -0.016), P=0.00038]. Circulating macrophage inflammatory protein-1α (MIP-1α) levels and TB-BMD were negatively correlated [ß(95 %CI): -0.058(-0.092, -0.024), P=0.00074]. Weighted median and MR-Egger results were in line with the IVW results. We also found suggestive causal relationship (IVW P<0.05) between seven circulating cytokines and BMD at corresponding sites. No significant pleiotropy or heterogeneity was observed in our study. CONCLUSION: Our MR analyses indicated a causal effect between two circulating cytokines and BMD at corresponding sites (HGF and HE-BMD, MIP-1α and TB-BMD), along with suggestive evidence of a potential causality between seven cytokines and BMD at the corresponding sites. These findings would provide insights into the prevention and treatment of osteoporosis, especially immunoporosis.

Crosstalk between bone and the immune system.

Bone functions not only as a critical element of the musculoskeletal system but also serves as the primary lymphoid organ harboring hematopoietic stem cells (HSCs) and immune progenitor cells. The interdisciplinary field of osteoimmunology has illuminated the dynamic interactions between the skeletal and immune systems, vital for the maintenance of skeletal tissue homeostasis and the pathogenesis of immune and skeletal diseases. Aberrant immune activation stimulates bone cells such as osteoclasts and osteoblasts, disturbing the bone remodeling and leading to skeletal disorders as seen in autoimmune diseases like rheumatoid arthritis. On the other hand, intricate multicellular network within the bone marrow creates a specialized microenvironment essential for the maintenance and differentiation of HSCs and the progeny. Dysregulation of immune-bone crosstalk in the bone marrow environment can trigger tumorigenesis and exacerbated inflammation. A comprehensive deciphering of the complex "immune-bone crosstalk" leads to a deeper understanding of the pathogenesis of immune diseases as well as skeletal diseases, and might provide insight into potential therapeutic approaches.

Inflammatory response toward a Mg-based metallic biomaterial implanted in a rat femur fracture model.

The immune system plays an important role in fracture healing, by modulating the pro-inflammatory and anti-inflammatory responses occurring instantly upon injury. An imbalance in these responses can lead to adverse outcomes, such as non-union of fractures. Implants are used to support and stabilize complex fractures. Biodegradable metallic implants offer the potential to avoid a second surgery for implant removal, unlike non-degradable implants. However, considering our dynamic immune system it is important to conduct in-depth studies on the immune response to these implants in living systems. In this study, we investigated the immune response to Mg and Mg-10Gd in vivo in a rat femur fracture model with external fixation. In vivo imaging using liposomal formulations was used to monitor the fluorescence-related inflammation over time. We combine ex vivo methods with our in vivo study to evaluate and understand the systemic and local effects of the implants on the immune response. We observed no significant local or systemic effects in the Mg-10Gd implanted group compared to the SHAM and Mg implanted groups over time. Our findings suggest that Mg-10Gd is a more compatible implant material than Mg, with no adverse effects observed in the early phase of fracture healing during our 4-week study. STATEMENT OF SIGNIFICANCE: Degradable metallic implants in form of Mg and Mg-10Gd intramedullary pins were assessed in a rat femur fracture model, alongside a non-implanted SHAM group with special respect to the potential to induce an inflammatory response. This pre-clinical study combines innovative non-invasive in vivo imaging techniques associated with multimodal, ex vivo cellular and molecular analytics. The study contributes to the development and evaluation of degradable biometals and their clinical application potential. The study results indicate that Mg-10Gd did not exhibit any significant harmful effects compared to the SHAM and Mg groups.

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.

Unraveling the Intricacies of OPG/RANKL/RANK Biology and Its Implications in Neurological Disorders-A Comprehensive Literature Review.

The OPG/RANKL/RANK framework, along with its specific receptors, plays a crucial role in bone remodeling and the functioning of the central nervous system (CNS) and associated disorders. Recent research and investigations provide evidence that the components of osteoprotegerin (OPG), receptor activator of NF-kB ligand (RANKL), and receptor activator of NF-kB (RANK) are expressed in the CNS. The CNS structure encompasses cells involved in neuroinflammation, including local macrophages, inflammatory cells, and microglia that cross the blood-brain barrier. The OPG/RANKL/RANK trio modulates the neuroinflammatory response based on the molecular context. The levels of OPG/RANKL/RANK components can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectants following brain injuries and also participate in the regulation of body weight, internal body temperature, brain ischemia, autoimmune encephalopathy, and energy metabolism. Although the OPG/RANKL/RANK system is primarily known for its role in bone remodeling, further exploring deeper into its multifunctional nature can uncover new functions and novel drug targets for diseases not previously associated with OPG/RANKL/RANK signaling.

Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration.

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.

Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging.

PURPOSE OF THE REVIEW: In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease. RECENT FINDINGS: Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.

Identifying the causal relationship between immune factors and osteonecrosis: a two-sample Mendelian randomization study.

A wealth of evidence intimates a profound connection between the immune system and osteonecrosis, albeit the specific immune factors underlying this connection remain largely veiled. A bidirectional Mendelian randomization (MR) study was conducted based on genome-wide association study summary data to identify causal links between 731 immune factors and osteonecrosis including drug-induced osteonecrosis. Preliminary MR analysis was accomplished utilizing the inverse-variance weighted method under a multiplicative random effects model, and heterogeneity and potential horizontal pleiotropy were evaluated through Cochrane's Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Upon false discovery rate correction, the gene-predicted level of one immune factor (CD62L - monocyte %monocyte) exhibited a significant positive correlation with osteonecrosis, while eight immune traits associated with monocytes, dendritic cells, and NK cells demonstrated significant causal effects with drug-induced osteonecrosis. Reverse MR revealed no significant correlations. This MR research provides genetic evidence for the causal associations between a broad spectrum of immune factors and osteonecrosis. Such a study aids in unraveling the intricate interaction patterns between the immune and skeletal systems, elucidating the pathogenesis of osteonecrosis, and identifying potential novel therapeutic approaches.