Figure 3 - available via license: CC BY
Content may be subject to copyright.
Source publication
Bone infection and inflammation leads to the infiltration of immune cells at the site of infection, where they modulate the differentiation and function of osteoclasts and osteoblasts by the secretion of various cytokines and signal mediators. In recent years, there has been a tremendous effort to understand the cells involved in these interactions...
Similar publications
Immune imbalance caused bone loss. Osteoimmunology is emerging as a new interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, T lymphocytes (T cells) play pivotal roles in the regulation of bone health. However, the roles and mechanisms of T cells in the treatment of osteopo...
Citations
... After bone resorption is complete, osteoclast apoptosis follows, and macrophage-like cells drift to the resorbed area to remove any remaining osteoclast-generated debris in a step called reversal. During the end stages of the reversal process, when the osteoclast-mediated bone resorption wanes, osteoclasts secrete sphingosine 1-phosphate, which incites osteoblast recruitment [32]. Next, more osteoblasts are recruited to the resorbed site, where they assemble a new inorganic matrix, and the subsequent mineralization fills up the resorption lacuna during formation. ...
... Next, more osteoblasts are recruited to the resorbed site, where they assemble a new inorganic matrix, and the subsequent mineralization fills up the resorption lacuna during formation. After formation, the bone remodeling cycle concludes with the termination phase, whereby osteoblasts have three possible fates, meaning that they undergo apoptosis, transform into bone lining cells, or become trapped into the bone matrix, where they end up differentiating into osteocytes [30,32]. The bone matrix-embedded osteocytes will control and coordinate future events of bone remodeling [32]. ...
... After formation, the bone remodeling cycle concludes with the termination phase, whereby osteoblasts have three possible fates, meaning that they undergo apoptosis, transform into bone lining cells, or become trapped into the bone matrix, where they end up differentiating into osteocytes [30,32]. The bone matrix-embedded osteocytes will control and coordinate future events of bone remodeling [32]. ...
Background:
Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.
Purpose of review:
This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.
Future perspectives:
The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
... However, TGF-β has also been identified to contribute to the angiogenesis of fracture-healing tissue. During osteoclastogenesis, RANKL drives osteoclast differentiation, while OPG antagonizes RANKL action, and the RANKL/OPG ratio affects the osteoclast differentiation rate and bone resorption process [96,97]. Different concentrations of TGF-β have different effects on the RANKL/OPG ratio and ultimately on osteoclast differentiation (low concentrations of TGF-β increase the stimulation of osteoclast differentiation, while high concentrations of TGF-β have the opposite effect) [98,99]. ...
The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of cytokines, such as pro-inflammatory factors and proteases. It is a crucial feature of senescent cells. SASP factors induce tissue remodeling and immune cell recruitment. Previous studies have focused on the beneficial role of SASP during embryonic development, wound healing, tissue healing in general, immunoregulation properties, and cancer. However, some recent studies have identified several negative effects of SASP on fracture healing. Senolytics is a drug that selectively eliminates senescent cells. Senolytics can inhibit the function of senescent cells and SASP, which has been found to have positive effects on a variety of aging-related diseases. At the same time, recent data suggest that removing senescent cells may promote fracture healing. Here, we reviewed the latest research progress about SASP and illustrated the inflammatory response and the influence of SASP on fracture healing. This review aims to understand the role of SASP in fracture healing, aiming to provide an important clinical prevention and treatment strategy for fracture. Clinical trials of some senolytics agents are underway and are expected to clarify the effectiveness of their targeted therapy in the clinic in the future. Meanwhile, the adverse effects of this treatment method still need further study.
... In this study, we found that three types of immune cells in the GSE152293 dataset, including naïve CD4 + T cells, activated dendritic cells, and neutrophils significantly differed between the two groups of patients. T cells have a central role in the interaction pathway of osteoclast formation, osteoclast formation, and bone remodeling [50]. Activated dendritic cells contribute to inflammation-mediated osteoclastogenesis and take part in inflammatory bone disease, which can activate T-cells by acting as APCs. ...
Background
Osteoporosis is the most common metabolic bone disease in humans. Exploring the expression difference of iron metabolism-related genes in osteoporosis can provide a new target for diagnosis and treatment.
Methods
First, we used online databases to identify differentially expressed genes (DEGs) related to iron metabolism in patients with osteoporosis. The differential genes were comprehensively analyzed by bioinformatics method (GO, KEGG, GSEA, immune infiltration analysis, PPI). The expression levels of hub genes and important signaling pathways were verified by qRT-PCR and Western blotting.
Results
A total of 23 iron metabolism-related genes with significant differences were identified, which were enriched in “regulation of protein dephosphorylation” and “negative regulation of protein dephosphorylation”. The GSEA results, heme metabolism and Myc targets v1 were among the top two pathways, both upregulated. The immune infiltration analysis revealed that the expressions of genes such as ABCA5, D2HGDH, GNAI2, and CTSW were correlated with the infiltration degree of significantly different cells. The PPI network contained 12 differentially expressed iron metabolism-related genes. Additionally, YWHAE, TGFB1, PPP1R15A, TOP2A, and CALR were mined as hub genes using the Cytoscape software. qRT PCR showed that the expression of TGF-β1, YWHAE, TOP2A and CALR increased. We also verified the expression of related proteins and genes in the oxidative stress signaling pathway by qRT PCR and Western blotting. The results showed that Mob1, YAP and TAZ molecules were highly expressed at the gene and protein levels.
Conclusions
These differentially expressed iron metabolism-related genes could provide new potential targets for the diagnosis and treatment of osteoporosis.
... However, exposure to an osteoclast-like medium induced the expression of a particular miRNA signature. Particularly, the miR-20a, miR-30d, miR-320a, miR-185, miR-130b, miR-155, miR-300, miR-222, and miR-33a expression levels were significantly down-regulated in fibroblasts, as revealed by the miRNAs array (Kumar & Roger, 2019). Moreover, Huang et al. recently revealed that the expression of mir-29a, modulating osteogenic differentiation, is elevated in PBMCs from AS patients compared to RA patients and healthy controls, implying its role as a potential biomarker for bone development in AS . ...
Inflammatory arthritis commonly initiates in the soft tissues lining the joint. This lining swells, as do the cells in it and inside the joint fluid, producing chemicals that induce inflammation signs such as heat, redness, and swelling. MicroRNA (miRNA), a subset of non-coding small RNA molecules, post-transcriptionally controls gene expression by targeting their messenger RNA. MiRNAs modulate approximately 1/3 of the human genome with their multiple targets. Recently, they have been extensively studied as key modulators of the innate and adaptive immune systems in diseases such as allergic disorders, types of cancer, and cardiovascular diseases. However, research on the different inflammatory joint diseases, such as rheumatoid arthritis, gout, Lyme disease, ankylosing spondylitis, and psoriatic arthritis, remains in its infancy. This review presents a deeper understanding of miRNA biogenesis and the functions of miRNAs in modulating the immune and inflammatory responses in the above-mentioned inflammatory joint diseases. According to the literature, it has been demonstrated that the development of inflammatory joint disorders is closely related to different miRNAs and their specific regulatory mechanisms. Furthermore, they may present as possible prognostic and diagnostic biomarkers for all diseases and may help in developing a therapeutic response. However, further studies are needed to determine whether manipulating miRNAs can influence the development and progression of inflammatory joint disorders.
... In this regard, social and behavioural characteristics are key factors related to the sex gap in mortality 43 . Studies in the field of osteoimmunology provide information regarding the modulating effect of the innate and adaptive immune system on bone resorption during inflammations 44 . In men and women, the development and functioning of the immune system are affected in distinct ways by various environmental factors, such as the nutrition status and the composition of the microbiome. ...
Postoperative complications following mandibular fracture treatment vary from local wound infections to severe conditions including osteomyelitis and impaired fracture healing. Several risk factors have been associated with the development healing disorders, including fracture localisation, treatment modality and substance abuse. However, limited research on the sex-specific influence of these complications exists. A total of about 300,000 female and male patients with mandibular fractures were examined in two cohorts. After matching for confounders (age, nicotine and alcohol dependence, malnutrition, overweight, anaemia, diabetes, osteoporosis and vitamin D deficiency), two cohorts were compared with propensity-score-matched patients according to outcomes (osteomyelitis, pseudoarthrosis and disruption of the wound) within 1 year after fracture. There were significant differences between female and male patients regarding the occurrence of osteomyelitis (odds ratio [OR] [95% confidence interval]: 0.621 [0.563; 0.686]) and disruption of the wound (OR [95% confidence interval]: 0.703 [0.632; 0.782]). Surprisingly, matching for the expected confounders did not change the results substantially. Sex plays a dominant role in determining the risk stratification for postoperative osteomyelitis and disruption of the wound, after accounting for other potential confounding factors. Additional research is needed to understand the underlying mechanisms and to develop sex-specific strategies to prevent these complications.
... 4,17 M1-induced activation leads to the synthesis and secretion of enzymes from osteoblast, such as matrix metalloproteinases (MMPs), that can break down the extracellular matrix of bone and lead to the resorption of bone tissue. 18 The in vitro, in vivo, and clinical studies further demonstrated that the presence of M1 macrophages triggers osteoblasts to express the receptor activator of nuclear factor-kB ligand (RANKL), a soluble cytokine essential for osteoclast differentiation from M1 macrophages. ...
In periodontitis, the bone remodeling process is disrupted by the prevalent involvement of bacteria-induced pro-inflammatory macrophage cells and their interaction between osteoblast cells residing within the infected bone tissue. The complex interaction between the cells needs to be deciphered to understand the dominant player in tipping the balance from osteogenesis to osteoclastogenesis. Yet, only a few studies have looked at the crosstalk interaction between osteoblasts and macrophages using biomimetic three-dimensional (3D) tissue-like matrices. In this study, we created a cell-laden 3D tissue analog to study indirect crosstalk between these two cell types and the direct synergistic effect when they were cultured together on a 3D scaffold. The cell-specific role on osteoclast differentiation was investigated through osteoblast- and pro-inflammatory macrophage-specific feedback studies. The results suggested that when macrophages were exposed to osteoblasts-derived conditioned media from the mineralized matrix, the M1 macrophages tended to maintain their pro-inflammatory phenotype. Further, when osteoblasts were exposed to secretions from pro-inflammatory macrophages, they demonstrated elevated Receptor activator of NF-kB ligand (RANKL) expression and decreased ALP activities compared to osteoblasts exposed to only osteogenic media. In addition, the upregulation of TNF-α and c-Fos in pro-inflammatory macrophages within the 3D matrix indirectly increased the RANKL expression and reduced the ALP activity of osteoblasts, which in turn promoted osteoclastogenesis. The contact co-culturing with osteoblast and pro-inflammatory macrophages within 3D matrix demonstrated that the pro-inflammatory markers (TNFα and IL1β) expressions were upregulated. In contrast, anti-inflammatory marker (CCL18) were downregulated and osteoclastic markers (TRAP 6 and ACP5) were unchanged. The data suggested that the osteoblasts curbed the osteoclastic differentiation of macrophages while macrophages still preserve their pro-inflammatory lineages. The osteoblast within the 3D co-culture demonstrated increased ALP activity and did not express RANKL significantly different than the osteoblast cultured within a 3D collagen matrix without macrophages. Contact co-culturing has an anabolic effect on bone tissue in a bacteria-derived inflammatory environment.
... Under bone infection and inflammatory conditions, both innate and adaptive immune cells can regulate bone resorption by secreting different inflammatory (IL-1β, TNF-α, IL-6, IL-17) and anti-inflammatory factors (IL-4, IL-10, and gamma interferon). Inflammatory cytokines stimulate osteoclast formation through the induction of RANKL, while antiinflammatory cytokines inhibit osteoclastogenesis and prevent bone loss [16]. ...
The analysis of bone microstructure and histological examination currently provides valuable insights into various facets of bone biology, ancient human existence, and bone-related diseases. This study aims to scrutinize the microstructure of historic Latvian bones, with three bone element groups selected (humerus, radius, and ulna) from a skeletal collection spanning from the Middle Ages to the Late Modern Period, procured through an archaeological excavation at St. George’s Church in Riga. To evaluate the changes in bone samples over time, two methods are utilized: (i) micro-computed tomography, used for measuring and calculating bone volume/trabecular volume (BV/TV), cortical bone and trabecular thickness, and trabecular pore diameter; (ii) immunohistochemistry (IHC) is employed to detect the presence of Runx2, OPG, OC, MMP2, TIMP2, BFGF, IL-1, IL-10, OPN, defensin-2, BMP 2/4, TGFβ factor in bone cells—specifically osteocytes. Archaeological human bone remains from the Middle Ages period in Latvia display a decline in the average bone volume to trabecular volume ratio when compared with the Late Modern Period, indicating a potential reduction in bone quality in the skeletons, potentially associated with a lower living standard during the earlier era. Comparing factors between the periods reveals a higher value of TIMP2 (p = 0.047) in samples from the Late Modern Period group, while IL-1 is higher (p = 0.036) in the Middle Ages group, which may suggest the presence of disease and diminished bone quality in the skeletons from the Middle Ages.
... Bone generation initiates with osteogenic differentiation of mesenchymal stem cells into osteoblasts [14]. Osteoblasts produce mineralization of bones, apart from expressing osteogenic and osteoclastogenic factors [27,39]. The incorporation of silicon, which is present in all tested membranes, has been shown to enhance both bioactivity and osteoblast-like cell activity [40]. ...
... M1 mainly secrete proinflammatory cytokines such as Tumor necrosis factor-α (TNF-α) and IL-1, IL-6 which are responsible for the recruitment of immune cells at the defect and initiation of the acute inflammatory response, leading to inflammation, tissue injury and fibrosis [51]. IL-10, related with M1 augmentation, plays a central role in tissue repair and neovascularization [13,52], increasing osteogenesis and decreasing osteoclastogenesis via activating exosomal IL-10 mRNA to cells, directly [13,39,53]. Thereby, M1 lay the foundation for subsequent bone tissue repair [17]. ...
The main target of bone tissue engineering is to design biomaterials that support bone regeneration and vascularization. Nanostructured membranes of (MMA)1-co-(HEMA)1/(MA)3-co-(HEA)2 loaded with 5% wt of SiO2-nanoparticles (Si-M) were doped with zinc (Zn-Si-M) or doxycycline (Dox-Si-M). Critical bone defects were effectuated on six New Zealand-bred rabbit skulls and then they were covered with the membranes. After six weeks, a histological analysis (toluidine blue technique) was employed to determine bone cell population as osteoblasts, osteoclasts, osteocytes, M1 and M2 macrophages and vasculature. Membranes covering the bone defect determined a higher count of bone cells and blood vessels than in the sham group at the top regions of the defect. Pro-inflammatory M1 appeared in a higher number in the top regions than in the bottom regions, when Si-M and Dox-Si-M were used. Samples treated with Dox-Si-M showed a higher amount of anti-inflammatory and pro-regenerative M2 macrophages. The M1/M2 ratio obtained its lowest value in the absence of membranes. On the top regions, osteoblasts were more abundant when using Si-M and Zn-Si-M. Osteoclasts were equally distributed at the central and lateral regions. The sham group and samples treated with Zn-Si-M attained a higher number of osteocytes at the top regions. A preferential osteoconductive, osteoinductive and angiogenic clinical environment was created in the vicinity of the membrane placed on critical bone defects.
... Anti-cytokine biological therapy's effectiveness mainly demonstrates the biological theory that a reduction in the release of a cytokine can slow down an inflammatory process in patients with inflammatory bone diseases. Recently, the identification of new pro-inflammatory signal transduction pathways has allowed the development of a new and very interesting therapeutic target [95,96]. Currently, in accordance with all the new knowledge acquired in the field of the pathogenesis of the periodontal disease, several biological drugs used for the treatment of other chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease, are being evaluated. ...
The principles of periodontal therapy are based on the control of microbial pathogens and host factors that contribute to biofilm dysbiosis, with the aim of modulating the progression of periodontitis and periodontal tissue destruction. It is currently known how differently each individual responds to periodontal treatment, depending on both the bacterial subtypes that make up the dysbiotic biofilm and interindividual variations in the host inflammatory response. This has allowed the current variety of approaches for the management of periodontitis to be updated by defining the goals of target strategies, which consist of reducing the periodontopathogenic microbial flora and/or modulating the host-mediated response. Therefore, this review aims to update the current variety of approaches for the management of periodontitis based on recent target therapies. Recently, encouraging results have been obtained from several studies exploring the effects of some targeted therapies in the medium- and long-term. Among the most promising target therapies analyzed and explored in this review include: cell-based periodontal regeneration, mediators against bone resorption, emdogain (EMD), platelet-rich plasma, and growth factors. The reviewed evidence supports the hypothesis that the therapeutic combination of epigenetic modifications of periodontal tissues, interacting with the dysbiotic biofilm, is a key step in significantly reducing the development and progression of disease in periodontal patients and improving the therapeutic response of periodontal patients. However, although studies indicate promising results, these need to be further expanded and studied to truly realize the benefits that targeted therapies could bring in the treatment of periodontitis
... In our study, LPS was injected on the surfaces of mice's calvarias to create inflammatory bone erosion models. We inspected that several osteoclasts generated on the inflammatory bone surface, accompanying large amounts of inflammatory cytokines produced and released by multiple immune cells, which was in line with the previous study (Kumar and Roger, 2019). The evidence is clear that some proinflammatory cytokines, like TNF and IL-1, regulate the activation of calcium signaling and NFATc1, which subsequently activate genes related to osteoclastogenesis and osteoclast function (Kim et al., 2013;Terkawi et al., 2022). ...
Abnormal activation and overproliferation of osteoclast in inflammatory bone diseases lead to osteolysis and bone mass loss. Although current pharmacological treatments have made extensive advances, limitations still exist. N-[2-bromo-4-(phenylsulfonyl)-3-thienyl]-2-chlorobenzamide (BNTA) is an artificially synthesized molecule compound that has antioxidant and anti-inflammatory properties. In this study, we presented that BNTA can suppress intracellular ROS levels through increasing ROS scavenging enzymes SOD1 and SOD2, subsequently attenuating the MARK signaling pathway and the transcription of NFATc1, leading to the inhibition of osteoclast formation and osteolytic resorption. Moreover, the results also showed an obvious restrained effect of BNTA on RANKL-stimulated proinflammatory cytokines, which indirectly mediated osteoclastogenesis. In line with the in vitro results, BNTA protected LPS-induced severe bone loss in vivo by enhancing scavenging enzymes, reducing proinflammatory cytokines, and decreasing osteoclast formation. Taken together, all of the results demonstrate that BNTA effectively represses oxidation, regulates inflammatory activity, and inhibits osteolytic bone resorption, and it may be a potential and exploitable drug to prevent inflammatory osteolytic bone diseases.
