Search Results (64)

Proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are key mediators of inflammatory bone loss and are commonly described as inhibitors of osteoblast function. However, their effects on osteogenesis remain controversial, likely due to the differences in the cell models and experimental settings in in vitro studies. We recently showed that these cytokines significantly enhanced the mineralization of primary human osteoblast-like cells (OBs). Here, we provide the first analysis of cytokine effects on the osteogenesis of the widely used human osteoblastic cell line hFOB 1.19 and compare them to primary OBs. Unexpectedly, all three cytokines significantly inhibited mineralization in hFOB 1.19 cells without affecting the proliferation. IL-1β and TNF-α also suppressed ALP activity, whereas IL-6 acted ALP-independent but increased the osteogenic marker expression despite the reduced mineralization, indicating a possible uncoupled differentiation and mineralization. Morphological and transcriptional analyses indicated that hFOB 1.19 cells represent an earlier osteogenic differentiation stage, while primary OBs show phenotypic heterogeneity and donor-dependent expression profiles. These data demonstrate that proinflammatory cytokines can have severely different effects on the osteogenesis of different cell models, supported by the highly contradictory findings reported in the literature. Nevertheless, elucidating the mechanisms underlying the inhibition of osteogenesis in hFOB 1.19 cells may provide important insights into the cell model and differentiation-stage-specific cytokine effects. Full article

Osteoporosis is a systemic bone disorder characterized by decreased bone mass and deteriorated microarchitecture, leading to an increased risk of fractures. Recent studies have revealed that its pathogenesis involves complex biological processes beyond bone remodeling, including oxidative stress, chronic inflammation, cellular senescence, osteoimmunology, gut microbiota alterations, and epigenetic modifications. Oxidative stress disrupts bone homeostasis by promoting excessive free radical production and osteoclast activity. Chronic inflammation and the accumulation of senescent cells impair skeletal repair mechanisms. Advances in osteoimmunology have highlighted the critical role of immune–bone crosstalk in regulating bone resorption and formation. Moreover, the gut–bone axis, mediated by microbial metabolites, influences bone metabolism through immune and endocrine pathways. Epigenetic changes, such as DNA methylation and histone modification, contribute to gene–environment interactions, affecting disease progression. Multi-omics approaches (genomics, proteomics, and metabolomics) systematically identify molecular networks and comorbid links with diabetes/cardiovascular diseases, revealing pathological feedback loops that exacerbate bone loss. In conclusion, osteoporosis pathogenesis extends beyond bone remodeling to encompass systemic inflammation, immunometabolic dysregulation, and gut microbiota–host interactions. Future research should focus on integrating multi-omics biomarkers with targeted therapies to advance precision medicine strategies for osteoporosis prevention and treatment. Full article

Osseointegration is the direct contact between living bone and a dental implant, with supporting evidence confirming the direct connection between bone and titanium, found using an electron microscope. However, the fundamental mechanisms and interconnections between the bone and titanium are not clearly understood. At present, osteoimmunology explores the interaction between bone and immune cells not only in the medical field but also in dentistry. Immunology in bone cell formation has long been a research topic; however, interest in these effects has recently surged. Through subsequent studies, osteoimmune reaction occurs in response to dental implant insertion into the bone and this mechanism portrays more accurate tissue response compared to the traditional term osseointegration. Additionally, osseointegration is a foreign body defense mechanism to protect the implant when bone forms at the contact surface between the dental implant and the alveolar bone. The term “osteoimmunology” refers to the relationship between the immune system and bone tissues. Understanding osteoimmunologic concepts may enable the development of immunomodulatory strategies to improve, maintain, and ultimately restore osseointegration. In order for biocompatible materials such as dental implants to settle and be maintained in the body, it is necessary to understand the complex interrelationships of the bone immune environment, which will enable the development of biomaterials that are more favorable to osteoimmune environments. Therefore, this review presents previous insights into cellular and molecular interactions between bone and the immune system, specifies the roles of T-regulatory cells (Tregs) and macrophages, and demonstrates their potential for translational applications worldwide. Full article

Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a member of the G-protein-coupled receptor (GPCR) family, has been implicated in various regulatory functions across multiple differentiation stages and numerous target sites in bone diseases. Therefore, LGR4 is a potential regulator of nuclear factor-κB ligand (RANKL) during osteoclast differentiation. However, a comprehensive investigation of its functions and applications in bone immunology is lacking. This review discusses the molecular characteristics, signaling pathways, and role of LGR4 in osteoimmunology, with a particular focus on its interactions with RANKL during osteoclast differentiation, while identifying gaps that warrant further research. Full article

Osteoclasts (OCs) are important therapeutic targets in the treatment of osteoporosis. The aim of this study was to explore a novel therapeutic approach for osteoporosis using Arcyriaflavin A (ArcyA), a natural compound derived from the marine invertebrate Eudistoma sp. We systematically evaluated the effects of ArcyA on OC differentiation and function in mouse models using molecular biology assays, cellular function analyses and in vivo animal experiments. We also evaluated the efficacy of ArcyA in human cells. The TRAP staining results provide the first clear evidence of the drug’s inhibitory effect, whereby the administration of ArcyA led to a significant reduction in TRAP-positive cells compared to the control group at concentrations that were non-toxic to bone marrow macrophages. Meanwhile, a significant reduction in the number of multinucleated giant cells with more than ten nuclei was observed. Furthermore, similar TRAP staining results were reproduced in human OCs, suggesting that ArcyA has the same effect on OCs derived from human PBMCs. At the molecular level, ArcyA treatment resulted in the downregulation of genes relevant to OC differentiation (NFATc1, cFos and TNFrsf11α), fusion and survival (DCstamp and ATP6v0d2) and resorption function (CTSK, MMP9, integrin β3 and ACP5). A western blot analysis of the corresponding proteins (NFATc1, cFos, CTSK and integrin β3) further confirmed the PCR results. Furthermore, ArcyA-treated OCs produced significantly fewer resorption pits, indicating suppressed bone resorption activity. Consistent with this, in vivo experiments using an ovariectomy (OVX)-induced osteoporosis mouse model showed that ArcyA treatment significantly alleviated bone loss. Mice in the treatment groups had higher BV/TV values, and this therapeutic effect was enhanced in a dose-dependent manner. In addition, our research also showed that IκB could be a potential target for the inhibitory effect of ArcyA. In conclusion, these findings suggest that ArcyA has significant therapeutic potential for the treatment of osteoporosis by inhibiting osteoclastogenesis and bone resorption. Further studies are warranted to explore its clinical applications. Full article

Background/Objectives: The COVID-19 pandemic has increased interest in osteoimmunology because of the impact of SARS-CoV-2 on both the immune system and the bone microenvironment. Soluble CD14ST could influence the production of the osteoimmunological regulators of osteoclast differentiation. The aim of this study is to evaluate the role of sCD14ST in COVID-19’s effects on bone remodeling—evaluating, in particular, the correlation with new-generation osteoimmunological biomarkers—and to acquire comprehensive knowledge of the effects of the disease on the immune and skeletal system. Methods: The serum level of sCD14ST was measured in COVID-19-positive and COVID-19-negative patients undergoing orthopedic surgery and correlated with the inflammatory and osteoimmunological biomarkers RANKL/OPG, FGF23, IL-6, C-reactive protein (CRP), procalcitonin (PCT), sRAGE, and SuPAR. Results: In our patients, sCD14ST showed a strong increase in COVID-19-positive patients, and a significant decrease in tandem with the infection resolution, confirming its diagnostic and prognostic value. sCD14ST was more clinically relevant than the two canonically inflammatory makers used in the clinical protocols, CRP and PCT, and displayed a good positive correlation with FGF23, RANKL/OPG, IL-6, and SuPAR and a negative correlation with sRAGE. Conclusions: Monitoring sCD14ST along with SuPAR may offer valuable insights into immune system dysregulation and bone-related complications in conditions characterized by inflammation. These soluble receptors represent important links between immune activation and bone metabolism, especially in the context of diseases like COVID-19, where the inflammatory response may impact bone fragility. Full article

Dental socket repair theoretically involves a constructive inflammatory immune response, which evolves from an initial M1 prevalence to a subsequent M2 dominance. In this scenario, the MEK1/2 signaling pathway is allegedly involved in M2 polarization. This study aimed to evaluate the impact of MEK1/2 pharmacological inhibition in the local host response and repair outcome. C57Bl/6-WT 8-week-old male mice were submitted to the extraction of the right upper incisor and treated (or not, control group) with MEK1/2 inhibitor PD0325901 (10 mg/kg/24 h/IP, MEK1/2i group) and analyzed at 0, 3, 7, and 14 days using microcomputed tomography, histomorphometry, birefringence, immunohistochemistry, and PCR array analysis. The results demonstrate that MEK1/2 inhibition limits the development of M2 response over time, being associated with lower expression of M2, MSCs, and bone markers, lower levels of growth and osteogenic factors, along with a higher expression of iNOS, IL-1b, IL-6, and TNF-α, as well inflammatory chemokines, indicating a predominantly M1 pro-inflammatory environment. This modulation of local inflammatory immune response is associated with impaired bone formation as demonstrated by microtomographic and histomorphometric data. The results show that MEK1/2 inhibition delays bone repair after tooth extraction, supporting the concept that M2 macrophages are essential elements for host response regulation and proper repair. Full article

Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment’s immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life. Full article

Osteoporosis is a progressive metabolic bone disease characterized by decreased bone density and microarchitectural deterioration, leading to an increased risk of fracture, particularly in postmenopausal women and the elderly. Increasing evidence suggests that inflammatory processes play a key role in the pathogenesis of osteoporosis and are strongly associated with the activation of osteoclasts, the cells responsible for bone resorption. In the present study, we investigated, for the first time, the influence of proinflammatory cytokines on the osteogenic differentiation, proliferation, and metabolic activity of primary human osteoblast-like cells (OBs) derived from the femoral heads of elderly patients. We found that all the proinflammatory cytokines, IL-1β, TNF-α, IL-6, and IL-8, enhanced the extracellular matrix mineralization of OBs under differentiation-induced cell culture conditions. In the cases of IL-1β and TNF-α, increased mineralization was correlated with increased osteoblast proliferation. Additionally, IL-1β- and TNF-α-increased osteogenesis was accompanied by a rise in energy metabolism due to improved glycolysis or mitochondrial respiration. In conclusion, we show here, for the first time, that, in contrast to findings obtained with cell lines, mesenchymal stem cells, or animal models, human OBs obtained from patients exhibited significantly enhanced osteogenesis upon exposure to proinflammatory cytokines, probably in part via a mechanism involving enhanced cellular energy metabolism. This study significantly contributes to the field of osteoimmunology by examining a clinically relevant cell model that can help to develop treatments for inflammation-related metabolic bone diseases. Full article

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. Full article

Osteomyelitis (OM) is a major challenge in orthopedic surgery. The diagnosis of OM is based on imaging and laboratory tests, but it still presents some limitations. Therefore, a deeper comprehension of the pathogenetic mechanisms could enhance diagnostic and treatment approaches. OM pathogenesis is based on an inflammatory response to pathogen infection, leading to bone loss. The present study aims to investigate the potential diagnostic role of a panel of osteoimmunological serum biomarkers in the clinical approach to OM. The focus is on the emerging infection biomarker sCD14-ST, along with osteoimmunological and inflammatory serum biomarkers, to define a comprehensive biomarker panel for a multifaced approach to OM. The results, to our knowledge, demonstrate for the first time the diagnostic and early prognostic role of sCD14-ST in OM patients, suggesting that this biomarker could address the limitations of current laboratory tests, such as traditional inflammatory markers, in diagnosing OM. In addition, the study highlights a relevant diagnostic role of SuPAR, the chemokine CCL2, the anti-inflammatory cytokine IL-10, the Wnt inhibitors DKK-1 and Sclerostin, and the RANKL/OPG ratio. Moreover, CCL2 and SuPAR also exhibited early prognostic value. Full article

Bone healing occurs through three consecutive and interdependent phases. While the acute inflammatory response is vital to fracture healing, chronic and systemic inflammation negatively affect the healing process. The bone tissue relies heavily on the immune system for its normal physiology and turnover. The interactions are more pronounced in injury states, such as fractures and autoimmune disorders. Recently, the field of osteoimmunology, the study of the molecular interplay of the immune and skeletal systems, has gained much-needed attention to develop new therapeutic strategies to accelerate fracture healing and prevent the complications of fracture healing. This review provides an overview of the process of fracture healing and discusses the role of immune cells, their interplay with the released cytokines, and the current state of the art in the field of osteoimmunology. Full article

Rheumatoid arthritis (RA) is an ongoing inflammatory condition that affects the joints and can lead to severe damage to cartilage and bones, resulting in significant disability. This condition occurs when the immune system becomes overactive, causing osteoclasts, cells responsible for breaking down bone, to become more active than necessary, leading to bone breakdown. RA disrupts the equilibrium between osteoclasts and osteoblasts, resulting in serious complications such as localized bone erosion, weakened bones surrounding the joints, and even widespread osteoporosis. Antibodies against the receptor activator of nuclear factor-κB ligand (RANKL), a crucial stimulator of osteoclast differentiation, have shown great effectiveness both in laboratory settings and actual patient cases. Researchers are increasingly focusing on osteoclasts as significant contributors to bone erosion in RA. Given that RA involves an overactive immune system, T cells and B cells play a pivotal role by intensifying the immune response. The imbalance between Th17 cells and Treg cells, premature aging of T cells, and excessive production of antibodies by B cells not only exacerbate inflammation but also accelerate bone destruction. Understanding the connection between the immune system and osteoclasts is crucial for comprehending the impact of RA on bone health. By delving into the immune mechanisms that lead to joint damage, exploring the interactions between the immune system and osteoclasts, and investigating new biomarkers for RA, we can significantly improve early diagnosis, treatment, and prognosis of this condition. Full article

Based on the evidence of a significant communication and connection pathway between the bone and immune systems, a new science has emerged: osteoimmunology. Indeed, the immune system has a considerable impact on bone health and diseases, as well as on bone formation during grafts and its stability over time. Chronic inflammation induces the excessive production of oxidants. An imbalance between the levels of oxidants and antioxidants is called oxidative stress. This physio-pathological state causes both molecular and cellular damage, which leads to DNA alterations, genetic mutations and cell apoptosis, and thus, impaired immunity followed by delayed or compromised wound healing. Oxidative stress levels experienced by the body affect bone regeneration and maintenance around teeth and dental implants. As the immune system and bone remodeling are interconnected, bone loss is a consequence of immune dysregulation. Therefore, oral tissue deficiencies such as periodontitis and peri-implantitis should be regarded as immune diseases. Bone management strategies should include both biological and surgical solutions. These protocols tend to improve immunity through antioxidant production to enhance bone formation and prevent bone loss. This narrative review aims to highlight the relationship between inflammation, oxidation, immunity and bone health in the oral cavity. It intends to help clinicians to detect high-risk situations in oral surgery and to propose biological and clinical solutions that will enhance patients’ immune responses and surgical treatment outcomes. Full article

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge. In this study, we utilized lipopolysaccharide (LPS) to imitate locally and systemically pathogenic bacterial infection and examined the bone regeneration performance of LPS-associated mandibular and tibial bone regeneration impairment in FcγRIIB^−/− mice. Our results indicated that a loss of FcγRIIB alleviates bone regeneration in both mandibles and tibiae. After LPS induction, FcγRIIB^−/− mice were susceptible to impaired fracture healing in tibial and mandibular bones. LPS decreased the mineralization to collagen ratio in FcγRIIB^−/− mice, indicating a mineralization defect during bone repair. An osteoblast-associated gene (Col1a1) was attenuated in FcγRIIB-deficient mice, whereas Bglap, Hhip, and Creb5 were further downregulated with LPS treatment in FcγRIIB^−/− mice compared to FcγRIIB^−/− mice. Alpl and Bglap expression was dcreased in osteoblasts derived from bone chips. An osteoclast-associated gene, Tnfsf11/Tnfrsf11 ratio, ewas increased in LPS-induced FcγRIIB^−/− mice and in vitro. Furthermore, systemic LPS was relatively potent in stimulating production of pro-inflammatory cytokines including TNF-α, IL-6, and MCP-1 in FcγRIIB^−/− mice compared to FcγRIIB^−/− mice. The levels of TNF-α, IFN-β, IL-1α, and IL-17A were increased, whereas IL-10 and IL-23 were decreased in FcγRIIB^−/− mice treated locally with LPS. These findings suggest that both local and systemic LPS burden can exacerbate bone regeneration impairment, delay mineralization and skeletal repair, and induce inflammation in SLE patients. Full article