Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.

Diverse connective tissues exhibit hierarchical anisotropic structures that intricately regulate homeostasis and tissue functions for dynamic immune response modulation. In this study, remotely manipulable hierarchical nanostructures are tailored to exhibit multi-scale ligand anisotropy. Hierarchical nanostructure construction involves coupling liganded nanoscale isotropic/anisotropic Au (comparable to few integrin molecules-scale) to the surface of microscale isotropic/anisotropic magnetic Fe3O4 (comparable to integrin cluster-scale) and then elastically tethering them to a substrate. Systematic independent tailoring of nanoscale or microscale ligand isotropy versus anisotropy in four different hierarchical nanostructures with constant liganded surface area demonstrates similar levels of integrin molecule bridging and macrophage adhesion on the nanoscale ligand isotropy versus anisotropy. Conversely, the levels of integrin cluster bridging across hierarchical nanostructures and macrophage adhesion are significantly promoted by microscale ligand anisotropy compared with microscale ligand isotropy. Furthermore, microscale ligand anisotropy dominantly activates the host macrophage adhesion and pro-regenerative M2 polarization in vivo over the nanoscale ligand anisotropy, which can be cyclically reversed by substrate-proximate versus substrate-distant magnetic manipulation. This unprecedented scale-specific regulation of cells can be diversified by unlimited tuning of the scale, anisotropy, dimension, shape, and magnetism of hierarchical structures to decipher scale-specific dynamic cell-material interactions to advance immunoengineering strategies.

Overactivation of osteoclasts disrupt the delicate balance between bone-resorbing osteoclasts and bone-forming osteoblasts, resulting in development of osteoporosis and various inflammatory disorders, including rheumatoid arthritis, spondyloarthropathies, and psoriatic arthritis. While inhibiting osteoclastogenesis represents a promising therapeutic strategy, current treatments targeting the RANKL pathway (such as bisphosphonates and denosumab) are associated with severe side effects, necessitating the development of safer alternatives. We hypothesize that the compound (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (DPHB), derived from Alpinia officinarum Hance, can effectively inhibit RANKL-induced osteoclastic activity while maintaining a favorable safety profile. Through tartrate-resistant acid phosphatase (TRAP) staining and bone resorption pit assays, we demonstrate that DPHB inhibits osteoclast formation and function. Mechanistically, DPHB suppresses both NF-κB and MAPK signaling pathways while inhibiting NFATc1 activation and nuclear translocation, as evidenced by immunofluorescence staining, real-time PCR, and western blotting assays. In a LPS-induced inflammatory osteolysis mouse model, intraperitoneal administration of DPHB significantly alleviated bone destruction, confirmed through Micro-CT scanning, histological staining, and enzyme-linked immunosorbent assay (ELISA). Our findings establish DPHB as a promising osteoclast inhibitor for treating bone loss disorders through its dual suppression of osteoclastogenesis via NF-κB and MAPK signaling pathways and amelioration of inflammatory bone destruction.

Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2; R26GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6f/f; CX3CR1CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.

The risk of developing osteoporosis (OP) is increased in patients with rheumatoid arthritis (RA), which is associated with poorer prognosis and higher mortality. Many patients with RA may experience bone loss early in the disease course. Therefore, timely assessment of the risk of OP in RA patients is essential.

This is a retrospective study in which we collected information from 500 RA patients who underwent bone mineral density assessments at Longhua Hospital, Shanghai University of Traditional Chinese Medicine, from January 2018 to December 2022. Based on the data collection timeline, the first 70% of patients were assigned to the training set, while the remaining 30% were included in the validation set. The model was established using the training set and evaluated through plotting of the receiver operating characteristic curves, calibration curves, and clinical decision curves. Internal validation was performed by resampling the training set data 1,000 times using the bootstrap method, while internal hold-out validation was conducted using the validation dataset.

Ultimately, six variables were identified as independently associated with RA combined with OP (RA-OP): female sex, age, beta C-terminal cross-linked peptide (β-CTX), anti-cyclic citrullinated peptide antibody (ACPA), triglycerides (TG), and N-terminal propeptide of type I procollagen (PINP). The regression equation for the model is as follows: Logistic (RA-OP) = -8.703 + 0.946*female + 0.053*age + 0.004*β-CTX + 0.001*ACPA + 0.6*TG-0.008*PINP. The model demonstrated good discrimination (AUC = 0.819, 95% CI: 0.775-0.863) and calibration. In both internal and internal hold-out validation, the model also performed well, with AUC values of 0.814 (95% CI: 0.772-0.864) and 0.772 (95% CI: 0.697-0.847), respectively. Clinical decision curves indicated that the model outperformed both extreme curves, suggesting good clinical utility.

Our model is user-friendly and has shown good predictive performance in both internal and internal hold-out validation, offering new insights for the early screening and treatment of OP risk in RA patients.

Osteomyelitis is a deep bone tissue infection caused by pathogenic microorganisms, with the primary pathogen being methicillin-resistant Staphylococcus aureus (MRSA). Due to the tendency of the infection site to form biofilms that shield drugs and immune cells to kill bacteria, combined with the severe local inflammatory response causing bone tissue destruction, the treatment of osteomyelitis poses a significant challenge. Herein, we developed a remotely controlled nanotherapeutic (TLBA) with immunomodulatory to treat MRSA-induced osteomyelitis. TLBA, combined with baicalin and gold nanorods, is positively charged to actively target and penetrate biofilms. Near-infrared light (808 nm) triggers spatiotemporal, controllable drug release, while bacteria are eliminated through synergistic interaction of non-antibiotic drugs and photothermal therapy, enhancing bactericidal efficiency and minimizing drug resistance. TLBA eliminated nearly 100 % of planktonic bacteria and dispersed 90 % of biofilms under NIR light stimulation. In MRSA-induced osteomyelitis rat models, laser irradiation raised the infection site temperature to 50 °C, effectively eradicating bacteria, promoting M2 macrophage transformation, inhibiting bone inflammation, curbing bone destruction, and fostering bone tissue repair. In summary, TLBA proposes a more comprehensive treatment strategy for the two characteristic pathological changes of bacterial infection and bone tissue damage in osteomyelitis.

The efficacy of growth factor delivery-based therapies for bone tissue regeneration is frequently undermined by oxidative stress, especially under inflammatory conditions, which results in structure damage and function inactivation of growth factors. Herein, a straightforward and universal protective delivery strategy is proposed by employing the multiple physical interactions between epigallocatechin-3-gallate (EGCG) and growth factors (e.g., neuregulin-1/NRG-1) to efficiently form self-assembled particles (NE APs). NE APs provide sustained release of NRG-1 while protecting it from oxidative damage, preserving its biological functions of cell recruitment, migration, and angiogenesis. Additionally, NE APs leverage EGCG's ability to scavenge reactive oxygen species and maintain mitochondrial homeostasis, while synergistically enhancing TNF/NF-κB/JAK-STAT signaling pathways to support immune responses and osteogenic differentiation. In vivo experiments demonstrated that NE APs create a favorable microenvironment for bone regeneration through stem cell recruitment, angiogenesis, and immune modulation, effectively promoting the repair of inflammatory bone defects. This versatile protective delivery strategy, based on polyphenol and growth factor self-assembly, offers the potential to advance the application of growth factors in regenerative medicine.

This study aimed to examine the relationships of osteoporosis with Osteoporosis indices in elderly patients, and investigate the associations of novel inflammatory markers with variations of Osteoporosis indices. Senior citizens were recruited from the National Health and Nutrition Examination Survey (NHANES). Dual-energy X-ray absorptiometry was used to detect bone mineral density tests. Osteoporosis indices and diagnosis of osteoporosis were evaluated using multivariate weighted logistic regression models. Novel inflammatory markers were calculated based on lymphocyte, neutrophil, monocyte, platelet, and albumin counts. The relationships between the Osteoporosis indices and novel inflammatory markers were evaluated with multivariate weighted logistic regression models. Totally 837 elderly patients were enrolled, including 494 men and 343 women, and their weighted average age was 68.28 ± 7.60 years. Our results indicated that the osteoporosis indices were positively correlated with the presence of osteoporosis and that these three indices measured the severity of osteoporosis. After multivariate weighted logistic regression model analysis of the novel inflammatory markers and osteoporosis index, AIRI, SIRI, and SII were significantly correlated with the osteoporosis indices. There may be a close relationship between inflammation and senile osteoporosis. The novel inflammatory markers are convenient and objective for predicting low BMD or osteoporosis risk in older patients. Among these markers, elderly patients with high levels of AISI, SIRI, and SII should focus on the risk of osteoporosis. However, this study has some limitations. It is essential to expand the sample size to a wider population to investigate the relationship between inflammation and osteoporosis.

Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, the key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito-loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplies Mito as well as O2 to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation. STATEMENT OF SIGNIFICANCE: The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, we develop a method for encapsulating mitochondria within erythrocytes, termed mitochondria-loading erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O2 to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.

Chronic infectious bone destruction diseases, such as periodontitis, pose a significant global health challenge. Repairing the bone loss caused by these chronic infections remains challenging. In addition to pathogen removal, regulating host immunity is imperative. The retention of neutrophil extracellular traps (NETs) in chronic infectious niches is found to be a barrier to inflammation resolution. However, whether ruining the existing NETs within the local infectious bone lesions can contribute to inflammation resolve and bone repair remains understudied. Herein, a nanocapsuled delivery system that scavenges NETs dual-responsively to near-infrared light as a switch and to NETs themselves as a microenvironment sensor is designed. Besides, the photothermal and photodynamic effects endow the nanocapsules with antibacterial properties. Together with the ability to clear NETs, these features facilitate the restoration of the normal host response. The immunocorrective properties and inherent pro-osteogenic effects finally promote local bone repair. Together, the NET scavenging nanocapsules address the challenge of impaired bone repair in chronic infections due to biased host response caused by excessive NETs. This study provides new concepts and strategies for repairing bone destruction attributable to chronic infections via correcting biased host responses in chronic infectious diseases.

A20, also known as TNF-α-induced protein 3 (TNFAIP3), is a crucial negative regulator of inflammation and immune responses. Emerging evidence suggests that A20 is involved in the regulation of glucose metabolism and plays a significant role in bone metabolic diseases by inhibiting nuclear factor (NF)-κB activation. However, the potential relationship between serum A20 level and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM) has not been explored. This study aims to investigate the association between serum A20 level with BMD and bone turnover markers (BTMs) in patients with T2DM.

A total of 189 patients with T2DM and 183 non-diabetic individuals were included in the study based on the inclusion and exclusion criteria. Participants were categorized into normal BMD and low BMD groups. Baseline clinical histories were collected through face-to-face questionnaires. Participants underwent measurements of blood biochemistry and anthropometric, hand grip strength records and short physical performance battery (SPPB) assessment. Serum A20 level was quantified by enzyme-linked immunosorbent assay kit. Areal BMD was measured using dual-energy x-ray absorptiometry (DXA). A T-score of less than -1.0 at the lumbar spine 1-4, femoral neck and/or total hip was classified as low BMD.

Serum A20 level was lower in patients with T2DM compared to controls [41.30 (29.91, 61.87) vs 76.01 (54.90, 109.64) pg/mL, P<0.001]. Bivariate correlation analysis revealed that A20 level was not associated with SPPB but negatively correlated with waist-to-hip ratio (WHR). Pearson correlation analysis showed A20 level was positively correlated with lumbar spine 1-4 BMD in male diabetic patients (r=0.253, P=0.032). Multivariate regression analysis showed a positive association between serum A20 level and lumbar spine 1-4 BMD (Beta=0.047; 95% CI: 0.007-0.086; P=0.024) after multivariate adjustment. Logistic regression analysis showed that lower serum A20 level predicted low BMD in male patients with T2DM (OR: 0.22; 95% CI: 0.09-0.59; P=0.002).

Type 2 diabetic patients exhibited lower serum A20 level compared to non-diabetic individuals. In male patients with T2DM, serum A20 level showed a significant positive correlation with lumbar spine 1-4 BMD and could serve as an independent negative predictor for low BMD.

This study aims to investigate the relationship between the Systemic Inflammatory Response Index (SIRI) and bone mineral density (BMD) in children and adolescents aged 8-19 years.

A cross-sectional design was used, utilizing NHANES data from 2011-2016, including 3,205 participants aged 8 to 19 years. Weighted multivariable regression analysis was conducted to assess the association between SIRI and BMD at the lumbar spine, pelvis, trunk, and whole body. Additionally, smooth curve fitting was applied to examine the nonlinear relationship between SIRI and BMD, and subgroup analyses were performed to explore potential interaction effects and modifiers.

SIRI was significantly positively correlated with BMD at the pelvis, trunk, and whole body (p < 0.05). After adjusting for covariates, a one-unit increase in ln(SIRI) was associated with increases in BMD of 0.018 g/cm², 0.006 g/cm², and 0.005 g/cm² for the pelvis, trunk, and whole body, respectively. Nonlinear analysis revealed a saturation effect between ln(SIRI) and BMD, with a more pronounced impact at specific threshold values. Subgroup analysis indicated that gender, age, BMI and total calcium levels modulated the relationship between SIRI and BMD.

SIRI is significantly associated with BMD in children and adolescents, with a positive effect on BMD at specific threshold levels. This finding suggests that SIRI may serve as a potential biomarker for assessing the risk of low bone mineral density, offering theoretical support for the prevention and intervention of bone health issues such as osteoporosis.

Osteoporosis is a common inflammation-related disease in which the release of proinflammatory cytokines promotes bone loss. Oleandrin is a monomer compound extracted from the leaves of the Nerium oleander plant, has been shown to exert an anti-inflammatory effect on a variety of inflammation-related diseases. However, its role in osteoporosis and the underlying mechanisms remain unclear. In this study, Oleandrin was shown to reduce bone loss in ovariectomy-induced osteoporotic mice in vivo. Additionally, Oleandrin inhibited RANKL-induced osteoclast differentiation in a concentration-dependent manner in vitro. Signalling pathway studies showed that Oleandrin could inhibit osteoclast differentiation by targeting MAPK and NF-κB signalling pathways. Further mechanistic studies showed that Oleandrin binds to low-density lipoprotein receptor-related protein 4 in osteoclast, thereby exerting inhibitory effects on osteoclast differentiation. In conclusion, this study lays the foundation for further research on the anti-inflammatory and anti-osteoporotic effects of Oleandrin on osteoporosis and its underlying mechanism and provides new possibilities for the treatment of osteoporosis.

We previously demonstrated that long-term trained immunity (TRIM) involves adaptations that imprint innate immune memory in long-lived myelopoiesis precursors and their progeny, monocytes/macrophages and neutrophils, which thereby acquire enhanced responsiveness to future challenges. Here, we show that a distinct component of myeloid biology, osteoclastogenesis, can also undergo innate immune training. Indeed, β-glucan-induced TRIM was associated with an increased osteoclastogenesis bias in the bone marrow and an expansion of monocytes/osteoclast progenitors in the periphery, resulting in aggravated severity of experimental periodontitis and arthritis. In the setting of trained inflammatory osteoclastogenesis, we observed transcriptomic rewiring in synovial myeloid cells of arthritic mice, featuring prominent upregulation of the transcription factor melanogenesis-associated transcription factor (MITF). Adoptive transfer of splenic monocytes from β-glucan-trained mice to naive recipients exacerbated arthritis in the latter in a strictly MITF-dependent manner. Our findings establish trained osteoclastogenesis as a maladaptive component of TRIM and potentially provide therapeutic targets in inflammatory bone loss disorders.

Current therapies targeting individual factors in inflammatory arthritis show variable efficacy, often requiring treatment with combinations of drugs, and are associated with undesirable side effects. NF-ĸB is critical for the production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF-ĸB is precarious. Hence, identifying pathways downstream of NF-ĸB that selectively govern the expression of inflammatory cytokines in inflammatory arthritis would be advantageous. We have previously identified IĸBζ as a unique inflammatory signature of NF-ĸB that controls the transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF-ĸB signals.

We generated mice harboring myeloid, lymphoid, and global deletion of Nfkbiz (the gene encoding IĸBζ). These models were subjected to serum transfer-induced arthritis. Additionally, pharmacologic inhibitors of IĸBζ were injected intraperitonially. Joint swelling, microcomputed tomography, immunohistochemistry, flow cytometry, and cytokine measurements were conducted using synovial tissue samples.

Global deletion of Nfkbiz or depletion of neutrophils (vastly IĸBζ+ cells) reduced inflammatory synovial cells and increased anti-inflammatory and regenerative synovial cells, plummeted expression of inflammatory factors and ameliorated experimental mouse inflammatory arthritis. Further, expression of immune responsive gene-1, the enzyme responsible for itaconate production, was increased in synovial cells. Accordingly, the itaconate derivative dimethyl itaconate (DI) inhibited IĸBζ-mediated inflammatory factors. Further, in silico screen identified 8-hydroxyquinoline (HQ) as a putative inhibitor of IĸBζ not affecting physiologic NF-ĸB activity. Congruently, systemic administration of either DI or HQ inhibited joint swelling and damage.

Our study positions IĸBζ as an inflammation-specific target for therapeutic consideration in rheumatoid arthritis because its inhibition spares the beneficial functions of NF-ĸB.

Immune-mediated inflammatory diseases (IMIDs) impose an immeasurable burden on individuals and society. While the conventional use of immunosuppressants and disease-modifying drugs has provided partial relief and control, their inevitable side effects and limited efficacy cast a shadow over finding a cure. Promising nucleic acid drugs have shown the potential to exert precise effects at the molecular level, with different classes of nucleic acids having regulatory functions through varying mechanisms. For the better delivery of nucleic acids, safe and effective viral vectors and non-viral delivery systems (including liposomes, polymers, etc.) have been intensively explored. Herein, after describing a range of nucleic acid categories and vectors, we focus on the application of therapeutic nucleic acid delivery in various IMIDs, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, asthma, ankylosing spondylitis, systemic lupus erythematosus, and uveitis. Molecules implicated in inflammation and immune dysregulation are abnormally expressed in a series of IMIDs, and their meticulous modulation through nucleic acid therapy results in varying degrees of remission and improvement of these diseases. By synthesizing findings centered on specific molecular targets, this review delivers a systematic elucidation and perspective towards advancing and utilization of nucleic acid therapeutics for managing IMIDs.

Osteoporotic fractures are a major public health concern, particularly among the aging population, as they significantly contribute to morbidity, mortality, and reduced quality of life. While cardiovascular health (CVH) has traditionally been linked to cardiovascular disease outcomes, emerging evidence suggests it may also influence bone health. This study investigates the association between CVH, as measured by the Life's Essential 8 (LE8) score, and the prevalence of osteoporotic fractures in U.S. adults. This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. A total of 17,606 adults aged 20 and above were included in the analysis after excluding participants with missing data on CVH or osteoporotic fractures. CVH was assessed using the LE8 score, which incorporates eight modifiable cardiovascular health metrics: diet, physical activity, tobacco use, sleep, body mass index (BMI), lipid levels, blood glucose, and blood pressure. The primary outcome, osteoporotic fractures, was identified through self-reported data confirmed by a physician. Weighted multivariate logistic regression models were used to estimate the association between CVH and the prevalence of osteoporotic fractures, adjusting for demographic and health-related covariates. Participants with higher CVH scores had a lower prevalence of osteoporotic fractures. In the fully adjusted model, each 1-point increase in the LE8 score was associated with a 1% reduction in the odds of osteoporotic fractures (OR = 0.99, 95% CI: 0.98-0.99). Compared to participants with low CVH levels, those with moderate CVH had a 22% lower odds of osteoporotic fractures (OR = 0.78, 95% CI 0.70-0.87), and those with high CVH had a 34% lower odds (OR = 0.66, 95% CI 0.56-0.79). A significant linear trend was observed across different CVH levels (P for trend < 0.001). Subgroup analyses revealed that the inverse relationship between CVH and osteoporotic fractures was consistent across different demographic and health-related subgroups. This study highlights a significant inverse association between cardiovascular health and osteoporotic fractures in U.S. adults. These findings suggest that maintaining a high level of cardiovascular health, as measured by the LE8 score, may be important in reducing the risk of osteoporotic fractures. Public health strategies that integrate cardiovascular and bone health interventions may enhance overall health outcomes and reduce the societal burden of both cardiovascular diseases and osteoporosis.

Overproduction of reactive oxygen species (ROS), elevated synovial inflammation, synovial hyperplasia and fibrosis are the main characteristic of microenvironment in rheumatoid arthritis (RA). Macrophages and fibroblast-like synoviocytes (FLSs) play crucial roles in the progression of RA. Hence, synergistic combination of ROS scavenging, macrophage polarization from pro-inflammatory M1 phenotype towards M2 anti-inflammatory phenotype, and restoring homeostasis of FLSs will provide a promising therapeutic strategy for RA. In this study, we successfully synthesized metformin-derived carbon dots (MCDs), and investigated the antirheumatic effect in vivo and in vitro. Designed MCDs could target inflamed cells and accumulate at the inflammatory joints of collagen-induced arthritis (CIA) rats. In vivo therapeutic investigation suggested that MCDs reduced synovial inflammation and hyperplasia, ultimately prevented cartilage destruction, bone erosion, and synovial fibrosis in CIA rats. In addition, MCDs eliminated the cellular ROS in M1 phenotype macrophages in RA microenvironment through the enzyme-like catalytic activity as well as inhibiting NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome signaling pathway, effectively polarizing them into the M2 phenotype to realize the anti-inflammatory effect. Furthermore, MCDs could inhibit the proliferation, migration, and fibrosis of inflamed FLSs. Mechanistically, MCDs restored the homeostasis of FLSs while reducing the level of synovial inflammation by blocking IL-6/gp130 signaling pathway. Combined with preferable biocompatibility, MCDs offer a prospective treatment approach for RA.

Infected alveolar bone defects pose challenging clinical issues due to disrupted intrinsic healing mechanisms. Thus, the employment of advanced biomaterials enabling the modulation of several aspects of bone regeneration is necessary. This study investigated the effect of multi-functional nanoparticles on anti-inflammatory/osteoconductive characteristics and bone repair in the context of inflamed bone abnormalities. Tannic-acid mineral nanoparticles (TMPs) were prepared by the supramolecular assembly of tannic acid with bioactive calcium and phosphate ions, which were subsequently incorporated into collagen plugs via molecular interactions. Under physiological conditions, in vitro analysis confirmed that tannic acid was dissociated and released, which significantly reduced the expression of pro-inflammatory genes in lipopolysaccharide (LPS)-activated RAW264.7 cells. Meanwhile, the bioactive ions of Ca2+ and PO43- synergistically increased the gene and protein expressions of osteogenic markers of bone marrow-derived stem cells. For in vivo studies, combined endodontic-periodontal lesions were induced in beagle dogs where the plugs were readily implanted. After 2 months of the implantation, analysis of micro-computed tomography and histomorphometry revealed that groups of dogs implanted with the plug incorporating TMPs exhibited a significant decrease in bone surface density as well as structural model index, and significant increase in the mineralized bone content, respectively, with positive OPN expression being observed in reversal lines. Notably, the profound improvement in bone regeneration relied on the concentration of TMPs in the implants, underscoring the promise of multi-functional nanoparticles for treating infected alveolar bones.

Pulmonary and extrapulmonary manifestations have been reported following infection with SARS-CoV-2, the causative agent of COVID-19. The virus persists in multiple organs due to its tropism for various tissues, including the skeletal system. This study investigates the effects of SARS-CoV-2 infection, including both ancestral and Omicron viral strains, on differentiating mesenchymal stem cells (MSCs), the precursor cells, into osteoblasts. Although both viral strains can productively infect osteoblasts, precursor cell infection remained abortive. Viral exposure during osteoblast differentiation demonstrates that both variants inhibit mineral and organic matrix deposition. This is accompanied by reduced expression of runt-related transcription factor 2 (RUNX2) and increased levels of interleukin-6 (IL-6), a cytokine that negatively regulates osteoblast differentiation. Furthermore, the upregulation of receptor activator of nuclear factor kappa B ligand (RANKL) strongly suggests that the ancestral and Omicron variants may disrupt bone homeostasis by promoting osteoclast differentiation, ultimately leading to the formation of bone-resorbing cells. This process is dependent of spike glycoprotein since its neutralization significantly reduced the effect of infective SARS-CoV-2 and UV-C inactivated virus. This study underscores the capacity of ancestral and Omicron SARS-CoV-2 variants to disrupt osteoblast differentiation, a process essential for preserving the homeostasis and functionality of bone tissue.

The purpose of this review is to summarize the current understanding of cell-autonomous innate immune pathways that contribute to bone homeostasis and disease.

Germ-line encoded pattern recognition receptors (PRRs) are the first line of defense against danger and infections. In the bone microenvironment, PRRs and downstream signaling pathways, that mount immune defense, interface intimately with the core cellular processes in bone cells to alter bone formation and resorption. The role of PRR engagement on bone remodeling has been best described as a result of activated macrophages secreting effector molecules that reshape the characteristics of bone-resident cells. However, it is being increasingly recognized that local bone resident-cells like osteoclasts and osteoblasts possess an arsenal of PRRs. The engagement of these PRRs by stimuli in the bone niche can drive cell-autonomous (aka cell-intrinsic) responses that, in turn, impact bone-remodeling dramatically, irrespective of immune cell effectors. Indeed, this vital role for cell-autonomous innate immune responses is evident in how reduced PRR activity within osteoclast progenitors correlates with their reduced differentiation and abnormal bone remodeling. Further, cell-intrinsic PRR activity has now been shown to influence the behavior of osteoblasts, osteocytes and other local immune/non-immune cell populations. However, distinct PRR families have varying impact on bone homeostasis and inflammation, emphasizing the importance of investigating these different nodes of innate immune signaling in bone cells to better identify how they synergistically and/or antagonistically regulate bone remodeling in the course of an immune response. Innate immune sensing within bone resident cells is a critical determinant for bone remodeling in health and disease.

Research on the link between inflammatory indicators and markers of bone metabolism is currently lacking, especially the interaction between Procollagen type 1 N-terminal propeptide (P1NP), the β-C-terminal telopeptide of type 1 collagen (β-CTX), and the fibrinogen-to-albumin ratio (FAR). This study intends to fill that knowledge gap by investigating the possible link between inflammatory indicators and bone metabolism.

This observational study included 718 individuals diagnosed with osteoporotic fractures from Kunshan Hospital Affiliated to Jiangsu University between January 2017 and July 2022. After accounting for several confounders, the independent connection between FAR levels and β-CTX and P1NP was investigated via Generalized Estimating Equations (GEE). On top of that, we used a generalized additive model (GAM) to find any non-linear correlations, and a two-piecewise linear regression model to find the threshold effects in the smoothing curves that came out of it. To ensure the aforementioned result was stable, a subgroup analysis was carried out.

The results showed a positive linear correlation between FAR and β-CTX [β = 1.077, 95% confidence interval (CI): 0.24 to 1.92, P = 0.012]. The study's findings demonstrated that FAR and P1NP fit curves in an inverted U-shaped pattern, and an inflection point K = 0.0685 for FAR was detected. P1NP showed a positive correlation with FAR below the inflection point (β = 306.10, 95% CI: 47.37 to 564.83, P = 0.021), and a negative correlation with FAR beyond the inflection point (β = -117.57, 95% CI: -231.34 to -3.80, P = 0.043). The subgroup analysis revealed that women had a more significant association between FAR and β-CTX in women than in men.

The results provide useful insights into the potential association between FAR and markers of bone metabolism. The study may provide a novel clinical implication by introducing FAR as a potential reference indicator for assessing bone health, offering a cost-effective and conveniently obtainable biomarker to monitor inflammation to improve bone metabolism in the treatment of osteoporosis.

Numerous observational studies have identified a link between osteoporosis and stroke. However, the causal genetic relationship between these conditions remains unclear. This study employs a two-sample bidirectional Mendelian randomization (MR) approach to ascertain the causal relationship between osteoporosis and stroke.

We conducted a two-sample Mendelian randomization (MR) study to investigate the potential causal relationship between osteoporosis and stroke, including its subtypes. Genetic data for osteoporosis and stroke, along with their subtypes, were sourced from published genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) demonstrating genome-wide significance (p < 5 × 10^ - 8) and independence (r^2 < 0.001) were selected for further analysis, provided they had an F-statistic ≥ 10. The inverse-variance weighted (IVW) method was employed to evaluate causality, with results reported as odds ratios (ORs). Heterogeneity was assessed using Cochran's Q test, while pleiotropy was tested using the MR-Egger intercept test. A leave-one-out sensitivity analysis was performed to ensure the robustness of the results.

Employing the IVW method, MR Egger method, and median-weighted method, we found no significant bidirectional causal relationship between osteoporosis and stroke or its subtypes, irrespective of the inclusion of potential pleiotropic SNPs. Sensitivity analyses affirmed the reliability and stability of these findings.

Our study findings indicate that there is no direct causal relationship between osteoporosis and stroke or its subtypes in either direction. Based on our results, although no direct link was found, secondary effects do exist.

Rheumatoid arthritis (RA) is a prevalent and currently incurable autoimmune disease. Existing conventional medical treatments are limited in their efficacy, prolonged disease may lead to bone destruction, joint deformity, and loss of related functions, which places a huge burden on RA patients and their families. For millennia, the use of traditional Chinese medicine (TCM), exemplified by the Gui-Zhi-Shao-Yao-Zhi-Mu decoction (GZSYZM), has been demonstrated to offer distinct therapeutic advantages in the management of RA. Exploring the potential mechanism of GZSYZM in the treatment of RA is a hot topic in the field of TCM.

High-throughput sequencing data of RA at bulk level and single cell level and Chinese Materia Medica target-related databases were used as data sources. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was employed for the identification of the most relevant compounds to the active ingredients present in the GZSYZM granules. Potential disease genes were identified using a combination of differential expression analysis and weighted gene co-expression network analysis, and the "Chinese Materia Medica-Ingredient-Target" network was constructed to obtain candidate drug target genes. The GZSYZM-RA hub genes were then identified based on Molecular Complex Detection algorithm. To explore the associations and potential mechanisms between the GZSYZM-RA hub gene set and RA, Mendelian randomization (MR) analysis and Bayesian co-localization analysis were used to further identify the GZSYZM-RA core genes that were causally associated with RA. A nomogram was constructed based on a multifactorial logistic regression model using the GZSYZM-RA core genes as predictors of RA. To evaluate its diagnostic value, receiver operating characteristic (ROC) curves, calibration curves, and decision curves were plotted. The potential downstream regulatory mechanisms of the gene of interest in GZSYZM in RA therapy were finally investigated using single- gene set enrichment analysis and molecular docking. The aim was to model the optimal conformation of its target protein receptor binding to the small molecule ligand in GZSYZM to identify the key constituents.

Functional enrichment analysis revealed that the GZSYZM-RA hub gene set is enriched in several autoimmune-related mechanistic pathways, with a particular emphasis on the phosphoinositide 3 kinase (PI3K)‑serine/threonine kinase (AKT) signaling pathway. AUCell scores demonstrated active expression of the GZSYZM-RA hub gene set with the PI3K-AKT signaling pathway on monocytes, especially non-classical monocytes. Immunol infiltration analysis based on the CIBERSORT algorithm also showed a strong correlation between several genes in the GZSYZM-RA hub gene set and monocytes by calculating Spearman's rank correlation coefficients. MR analysis with co-localization analysis further identified seven core genes (CASP8, PPARG, IKBKB, PPARA, IFNG, MYC, and STAT3) causally associated with RA. Diagnostic value for clinical decision making was demonstrated by a multivariable logistic regression model constructed with GZSYZM-RA core genes. Molecular docking analysis indicates that CASP8 and GZSYZM have high docking scores, with three key constituents (quercetin, kaempferol, and diosmetin) exhibiting strong binding affinities.

GZSYZM may regulate the abnormal over-proliferation and apoptotic imbalance of fibroblast-like synoviocytes in RA patients by inhibiting signaling of the PI3K-AKT signaling pathway while activating CASP8-mediated pro-apoptotic effects. And it may be effective in directly or indirectly inhibiting monocyte-to-osteoclast differentiation, ultimately improving the poor prognosis of joint destruction in RA patients.

A growing number of studies have highlighted the significance of human gut microbiota (GM) as a potential target for osteoporosis. In this review, we discuss the effect of GM to bone metabolism focusing on two aspects: the local alterations of the human gut permeability that modify how the GM interact with the gut-bone axis (e.g., intestinal leakage, nutrient absorption), and the alterations of the GM itself (e.g., changes in microbiota metabolites, immune secretion, hormones) that modify the events of the gut-bone axis. We then classify these changes as possible therapeutic targets of bone metabolism and highlight some associated promising microbiome-based therapies. We also extend our discussions into combinatorial treatments that incorporate conservative treatments, such as exercise. We anticipate our review can provide an overview of the current pathophysiological and therapeutic paradigms of the gut-bone axis, as well as the prospects of ongoing clinical trials for readers to gain further insights into better microbiome-based treatments to osteoporosis and other bone-degenerative diseases. The translational potential of this article: This paper reviewed the potential links between gut microbiota and osteoporosis, as well as the prospective therapeutic avenues targeting gut microbiota for osteoporosis management, presenting a thorough and comprehensive literature review.

Primary anterior cruciate ligament (ACL) reconstruction graft failure remains a significant health concern in young patients. Despite the high incidence of poor graft integration in these patients and the resulting high failure rate, little consideration has been given to the quality of the bone into which the graft is anchored at reconstruction. Therefore, we investigated post ACL injury mineralized tissue changes in the ACL femoral entheses of young males and compared them to changes previously reported for young females.

ACL femoral entheses and adjacent bone specimens were harvested from the injured knees of 51 young males during primary ACL reconstructive surgery and from 10 non-injured male cadaveric donors. The specimens were imaged via nano-computed tomography and analyzed for volumetric bone mineral density (vBMD) and architectural changes.

Male femoral ACL explant specimens had significantly lower cortical vBMD (p < 0.001), lower relative bone volume (BV/TV, p = 0.027) and greater cortical bone porosity (Ct.Po, p = 0.027) but similar trabecular bone parameters (p's > 0.05) to those of control specimens from male cadaveric donors. Cortical and trabecular bone loss increased significantly with time from ACL injury to reconstructive surgery (p's < 0.05). While cortical loss occurred in both males and females, significant trabecular loss occurred only in females (p = 0.009).

Femoral entheseal bone loss occurs in males following ACL injury. This bone loss increases with time following ACL injury, with cortical bone loss occurring sooner after injury than trabecular bone loss. The effects of ACL injury and time from injury to surgery on trabecular bone microarchitecture differed between male and female patients.

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Objective: To evaluate the drug release, cytocompatibility with periodontal ligament cells (PDLCs), and therapeutic efficacy of GelMA hydrogel loaded with resolvin D1 (RvD1) in treating rat periodontal inflammation and alveolar bone damage. Methods: An RvD1 complexed with GelMA was prepared, and its release kinetics and compatibility with PDLCs were assessed. Rats with induced periodontitis were treated weekly with topical applications of vehicle, GelMA, RvD1, or RvD1 complexed with GelMA for four weeks. Periodontal inflammation and tissue regeneration were evaluated using quantitative PCR (qPCR) and histochemical staining, while alveolar bone repair and regeneration were analyzed through micro-CT. Results: The RvD1 complexed with GelMA effectively released RvD1 and enhanced the proliferation and viability of PDLCs. Compared to RvD1 alone, treatment with RvD1 complexed with GelMA significantly reduced inflammatory cell infiltration, TNF-α and RANKL expression, and osteoclast formation in periodontal tissues. Additionally, it promoted the expression of specific anti-inflammatory and regenerative markers. Micro-CT analysis confirmed significant new bone formation in the RvD1 complexed with GelMA-treated group. Conclusions: RvD1 complexed with GelMA provides sustained drug release and biocompatibility, effectively resolves periodontal inflammation, and promotes tissue regeneration in periodontitis.

Patients with type 2 diabetes mellitus (T2DM) have increased hip fracture risk. And the association between urine albumin to creatinine ratio (ACR) and an increased risk of hip fracture in patients with T2DM remains controversial. This study aimed to investigate the association between urinary ACR and hip fracture risk in postmenopausal women and aged men with T2DM. The study included 219 postmenopausal women and 216 older men (mean age >60 years) with T2DM. Women and men were divided into control group (ACR<30 mg/g), microalbuminuria group (30 mg/g ≤ ACR<300 mg/g), and macroalbuminuria group (ACR≥300 mg/g) respectively. Demographic characteristics and clinical history were collected in patients. Biochemical indexes and bone turnover-related markers were measured in patients. In the study, we found that several factors, including age, T2DM duration, cerebral infarction history, serum corrected calcium levels and urine ACR were positively associated with hip fracture risk. However, 25-Hydroxyvitamin D and areal BMD were negatively associated with hip fracture risk. Furthermore, multiple regression analysis showed that urinary ACR level (β = 0.003, p = 0.044) and duration of T2DM (β = 0.015, p = 0.018) were positively and independently correlated with hip fracture risk in older men. In contrast, femoral neck BMD (β = -6.765, p < 0.001) was independently and negatively correlated with hip fracture risk in older men. This study indicated that the elevated ACR levels and longer T2DM duration were related to higher hip fracture risk in older men with T2DM, which could be beneficial for developing a predictive model for osteoporotic fractures in patients with type 2 diabetes in the future. However, results were inconsistent in women, hip fracture risk didn't alter by changes in urinary microalbuminuria level in postmenopausal women with T2DM.

Osteoporosis is an osteolytic disorder resulting from an inequilibrium between osteoblast-mediated osteogenesis and osteoclast-driven bone absorption. Safe and effective approaches for osteoporosis management are still highly demanded.

This study aimed to examine the osteoprotective effect and the mechanisms of phaseol (PHA) in vitro and in vivo.

Virtual screening identified the potential inhibitors of transforming growth factor-beta-activated kinase 1 (TAK1) from coumestans. The interaction between PHA and TAK1 was investigated by molecular simulation, pronase and thermal resistance assays. The maturation and function of osteoclasts were determined using tartrate-resistant acid phosphatase staining, bone absorption and F-actin ring formation assays. The differentiation and calcification of osteoblasts were assessed by alkaline phosphatase staining and Alizarin Red S staining. The activity of related targets and pathways were detected using immunoblotting, immunofluorescence and co-immunoprecipitation assays. The in vivo osteoprotective effect of PHA was evaluated using a lipopolysaccharide (LPS)-induced mouse osteoporosis model.

Firstly, we confirmed that TAK1 was essential in controlling bone remodeling by regulating osteogenesis and osteoclastogenesis. Moreover, PHA, a coumestan compound predominantly present in leguminous plants, was identified as a potent TAK1 inhibitor through virtual and real experiments. Subsequently, PHA was observed to enhance osteoblast differentiation and calcification, while suppress osteoclast maturation and bone resorptive function in vitro. Mechanistically, PHA remarkably inhibited the TRAF6-TAK1 complex formation, and inhibited the activation of TAK1, MAPK and NF-κB pathways by targeting TAK1. In the in vivo study, PHA strongly attenuated bone loss, inflammatory responses, and osteoclast over-activation in lipopolysaccharide-induced osteoporosis mice.

PHA had a dual-functional regulatory impact on osteogenesis and osteoclastogenesis by targeting TAK1, suppressing TRAF6-TAK1 complex generation, and modulating its associated signaling pathways, ultimately leading to mitigating osteoporosis. This study offered compelling evidence in favor of using PHA for preventing and managing osteoporosis as both a bone anabolic and anti-resorptive agent.

In this study, we tested the hypothesis that pre-osteoclast signaling is key in triggering post-traumatic angiogenesis in alveolar bone via the SDF-1/CXCR4 pathway. Interruption of osteoclast differentiation through zoledronate (Zol) disrupts the crosstalk between pre-osteoclasts and endothelial cells, hindering the initial angiogenic reaction following dental trauma. This disruption could therefore play a role in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ).

The effect of zoledronate on the expression of SDF1 was tested in pre-osteoclasts (POC) in vitro. Then, we tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone, using microCT-angiography and immunohistochemistry.

SDF-1 mRNA expression decreased in Zol-treated POCs (p = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12+ (SDF-1α) expressing POCs with Zol treatment (p = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs (p = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol (p = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration (p = 0.0012), and tube formation (p < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31+ HUVECs in Alveolar bone of Zol-treated rats (p = 0.0071), confirmed by significantly lower percentage of blood vessel volume (p = 0.026), and marginally lower vessel number (p = 0.062) in the alveolar bone.

Pre-osteoclasts play a crucial role in the initial angiogenic response in alveolar bone following dental extraction. Disruption of this process may be a predisposing factor to osteonecrosis.

Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve fiber density in the sciatic nerve, ankle joint synovium, and skin of naïve mice. Withdrawal responses to mechanical, thermal, and cold stimuli before and after joint inflammation induced by intra-articular injection of complete Freund adjuvant (CFA) were similar between human recombinant nerve growth factor-wild type and hNGF-R100E male and female mice while weight bearing and gait analysis revealed significant differences. Intriguingly, hNGF-R100E male and female mice showed only mild changes, indicating lower degrees of deep joint-related pain compared to their wild type counterparts. Furthermore, micro-CT analysis demonstrated that hNGF-R100E female mice, but not males, were protected from CFA-induced bone loss, and mRNA analysis showed a different gene regulation indicating a sex-dependent relationship between NGF, inflammation, and bone loss. In conclusion, our study reveals that the hNGF-R100E mutation renders mice insensitive to inflammation-induced impact on joint loading and gait while preserving the development of the peripheral nociceptive neurons and sensitivity to punctate stimulation of the skin. Notably, the mutation uncovers a sex-dependent relationship between NGF and inflammation-induced bone loss. These findings offer valuable insights into NGF as a target for pain management and the interplay between NGF and bone architecture.

This cross-sectional study investigated associations among the Healthy Eating Index (HEI)-2015, Dietary Inflammatory Index (DII), and body composition in female collegiate athletes.

Female NCAA Division I student-athletes (n = 41, 18-21 years old) were included from various sports and did not report any diagnosed chronic diseases.

Demographics, dietary intake, anthropometrics, and body composition, including bone mineral density, were collected utilizing a questionnaire, three interview-based multiple-pass 24-h dietary recalls, and dual-energy X-ray absorptiometry.

Mean HEI-2015 and DII scores (using 39 of 45 components) were 56.2 ± 13.5 and -0.1 ± 1.9, respectively. Athletes did not meet recommended intake levels for servings of fruit, vegetables, fiber, calcium, vitamin D, omega-3, and omega-6. Saturated fat and added sugar intake exceeded the recommended intakes. Diet quality indices and body composition measures were not correlated.

Although female collegiate athletes consumed poor-quality diets, this was not associated with body composition or bone health.

Investigate the relationship between bone mineral density (BMD) at various body sites and dental caries.

Based on the National Health and Nutrition Examination Survey (NHANES) database from 2011 to 2016, the correlation between BMD at various body sites and the DMFS index among 7044 adults aged 20-59 years was analyzed. Multiple linear regression, restricted cubic splines (RCS), piecewise linear regression, logistic regression, weighted quantile sum regression (WQS) and mediation effects analysis were integrated to explore the relationship between BMD and dental caries.

Under the linear assumption, except for arm BMD, the BMDs of all other sites are negatively correlated with the DMFS index of dental caries. RCS analysis indicates a U-shaped relationship between head BMD and the DMFS index (p for nonlinear < 0.0001). WQS analysis indicates that mixed BMD is significantly negatively correlated with the DMFS index for dental caries (estimate, - 0.023; 95% CI, - 0.025 ~ - 0.020), and head BMD has the most significant impact on the DMFS index (weight = 91.4%). Simple mediation analysis of the effect of dental caries on BMD levels mediated by inflammation levels showed negative results, suggesting that dental caries may not influence BMD through inflammation levels.

Monitoring BMD should be combined with appropriate oral healthcare and caries management strategies to effectively address these interconnected health issues, and particular attention should be paid to the monitoring of head BMD.

Excessive activity of osteoclasts(OCs) lead to bone resorption in chronic inflammatory conditions. The use of natural compounds to target OCs offers significant promise in the treatment or prevention of OC-associated diseases. Irilin D (IRD), a natural isoflavone derived from Belamcanda chinensis (L.) DC., has potential effects on OC differentiation both in vitro and in vivo that have yet to be thoroughly explored. In our study, we found that IRD inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC differentiation, actin ring formation, and bone resorption in vitro without compromising cell viability. However, IRD did not exhibit anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated macrophages. Furthermore, IRD reduced LPS-induced inflammatory bone loss by blocking osteoclastogenesis in a mouse model. Mechanistically, IRD disrupted RANKL-induced activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), leading to the inhibition of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. We also demonstrated that IRD inhibited RANKL-induced osteoclastic NFATc1 target genes, including DC-STAMP, ACP5, and CtsK. Our results indicate that IRD mitigates LPS-induced inflammatory bone resorption in mice by inhibiting RANKL-activated MAPKs and NF-κB signaling pathways, suggesting its potential as a natural isoflavone for preventing or treating OC-associated diseases.

Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss.

To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro.

CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163.

Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.