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Macrophage efferocytosis (clearance of apoptotic cells) is crucial for tissue homeostasis and wound repair, where macrophages secrete factors that promote resolution of inflammation and regenerative signalling. This study examined the role of efferocytic macrophage‐associated CCL2 secretion, its influence on mesenchymal stem/progenitor cell (MSPC) chemotaxis, and in vivo cell recruitment using Ccr2−/− (KO) mice with disrupted CCL2 receptor signalling in two regenerative models: ossicle implants and ulnar stress fractures. Single cell RNA sequencing and PCR validation indicated that efferocytosis of various apoptotic cells at bone injury sites (osteoblasts, pre‐osteoblasts, MSPC) upregulated CCL2. CCL2 gradients enhanced MSPC migration through type I collagen matrices. In vivo, MSPC (LepR+) infiltration was significantly reduced while macrophage (F4/80+) infiltration increased in KO ossicle implants versus WT. In ulnar stress fractures, micro‐CT revealed increased mineralized callus incidence in CCR2 KO male mice 5 days post injury (dpi) versus WT. By 7‐dpi callus fractional bone volume, trabecular thickness, and bone mineral density were increased versus WT. Immunohistochemistry of mice 5‐dpi confirmed an increase in callus area (including soft tissue); however, the percent of osteoprogenitors (%Osx+) within the callus was not different. These findings suggest that CCL2 differentially impacts MSPC recruitment depending on bone wound healing model. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bone marrow is pivotal for normal hematopoiesis and immune responses, yet it is often compromised by malignancies. The bone microenvironment (BME), composed of bone and immune cells, maintains skeletal integrity and blood production. The emergence of primary or metastatic tumors in the skeletal system results in severe complications and contributes significantly to cancer-related mortality. These tumors set off a series of interactions among cancer, bone, and immune cells, and disrupt the BME locally or distantly. However, the drivers, participants, and underlying molecules of these interactions are not fully understood. This review explores the crosstalk between bone metabolism and immune responses, synthesizing current knowledge on the intersection of cancer and osteoimmune biology. It outlines how bone marrow immune cells can either facilitate or hinder tumor progression by interacting with bone cells and pinpoints the molecules responsible for immunosuppression within bone tumors. Moreover, it discusses how primary tumors remotely alter the BME, leading to systemic immune suppression in cancer patients. This knowledge provides critical rationales for emerging immunotherapies in the treatment of bone-related tumors. Taken together, by summarizing the intricate relationship between tumor cells and the BME, this review aims to deepen the understanding of the diversity, complexity, and dynamics at play during bone tumor progression. Ultimately, it highlights the potential of targeting bone-tumor interactions to correct aberrant immune functions, thereby inhibiting tumor growth and metastasis.

Bingpeng Lin,1,2,* Yufei Fan,2,* Xuechao Yang,2 Janak L Pathak,2 Mei Zhong3 1Department of Orthodontics, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China; 2Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, People’s Republic of China; 3Department of Prosthodontics, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China*These authors contributed equally to this workCorrespondence: Janak L Pathak; Mei Zhong, Email J.pathak@gzhmu.edu.cn; 2016686043@gzhmu.edu.cnAbstract: Periodontal disease is a common disorder affecting a wide range of people and has a high prevalence globally. Periodontitis comprises a series of inflammatory conditions affecting periodontal support tissue, which could ultimately lead to tooth loss and reduce life quality and add to the financial burden of society. Matrix metalloproteinase-12 (MMP-12) is an elastase that is produced mostly by macrophages and could degrade a wide spectrum of extracellular matrix (ECM) and also contribute to several systematic pathological conditions. Recently, researchers have reported higher expression of MMP-12 in chronic periodontitis patients. However, there are few reports on the role of MMP-12 in periodontitis pathogenicity, and the interaction between MMP-12, periodontal pathogens, and periodontal tissues remains unclear. In this review, we introduce the potentially unique role of MMP-12 in the context of periodontal inflammation earlier, summarize the possible effects of MMP-12 on the pathological process of periodontitis and the interaction of host response under the challenge of various inflammatory factors, and provide possible diagnostic and therapeutic strategies targeting MMP-12 for the management of periodontitis. Future research and policies should focus on and implement effective chairside testing methods to reduce the prevalence of periodontal diseases.Keywords: matrix metalloproteinase-12, periodontitis, dysbiosis, epithelial barrier, immunity, osteoimmunology

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

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. [ABSTRACT FROM AUTHOR]

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

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

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. [ABSTRACT FROM AUTHOR]

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

Johann Lechner,1 Volker von Baehr,2 Florian Notter,1 Fabian Schick1 1Clinic for Integrative Dentistry, Munich, Germany; 2Department of Immunology and Allergology, Institute for Medical Diagnostics, Berlin, GermanyCorrespondence: Johann Lechner, Gruenwalder Str. 10A, Munich, 81547, Germany, Tel +49 89 697 0129, Fax +49 89 692 5830, Email drlechner@aol.comIntroduction: Osteoimmunology recognizes the relationship between bone cells and immune cells. Chronic osteoimmune dysregulation is present in bone marrow defects of the jaw (BMDJ) as fatty-degenerative osteonecrosis (FDOJ). In comparison to samples from healthy jaw bone, the cytokine analysis of samples of BMDJ/FDOJ from 128 patients showed downregulated TNF-α and IL-6 expression and the singular overexpression of the chemokine RANTES/CCL5.Aim and Objectives: This paper raises the question of whether the osteoimmune defects due to incomplete wound healing in BMDJ/FDOJ in 128 patients are related to dysregulation of the Th1/Th2 ratio and regulatory T cell (T-reg) expression in a control group of 197 BMDJ/FDOJ patients, each presenting with BMDJ/FJOD and one of seven different immune disorders.Material and Methods: In the control group, serum concentrations of the cytokines IFN-y and IL-4 were determined after stimulated cytokine release and displayed as Th1/Th2 ratios.Results: Data show a shift in Th2 in more than 80% (n = 167) of the control cohort of 197 chronically ill patients with concomitant BMDJ/FDOJ. In these 167 subjects, the Th1/Th2 ratio was < 6.1 demonstrating impaired immune regulation. Forty-seven subjects or 30% showed not only a shift in Th2 but also excessive T-reg overactivation with levels of > 1.900 pg/mL, indicating strongly downregulated immune activity.Discussion: BMDJ/FDOJ is characterized by a lack of Th1 cytokines and an excessive expression of RANTES/CCL5 and IL-1ra and, thus, the inversion of an acute inflammatory cytokine pattern. In contrast, abdominal fat contains a very high proportion of regulatory Th1 cells and produces an inflammatory immune response through the high overexpression of TNF-α and IL-6. The lack of Th1 activation in BMDJ/FDOJ areas inhibits normal wound healing and supports the persistence of BMDJ/FDOJ.Conclusion: The Th1/Th2 ratio requires greater consideration, especially with respect to wound healing following dental surgical interventions, such as jaw surgery, implantation and augmentation, to avoid the emergence of the osteoimmune situation that is characteristic of BMDJ/FDOJ. Keywords: osteoimmunology, T-cells, Th1/Th2 shift, jawbone, osteoclastogenesis, RANTES/CCL5

Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration. Similarly, in the setting of osteoarthritis, where degraded cartilage does not regenerate, therapeutic proteins hold great promise to promote new cartilage formation. For both osteoporosis and osteoarthritis treatments, targeted delivery of therapeutic growth factors, with the aid of hydrogels, to bone and cartilage is a key to advance the field of regenerative medicine. In this review article, we propose five important aspects of therapeutic growth factor delivery for bone and cartilage regeneration: (1) protection of protein growth factors from physical and enzymatic degradation, (2) targeted growth factor delivery, (3) controlling GF release kinetics, (4) long-term stability of regenerated tissues, and (5) osteoimmunomodulatory effects of therapeutic growth factors and carriers/scaffolds.

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. [ABSTRACT FROM AUTHOR]

Abstract Rare earth nanomaterials (RE NMs), which are based on rare earth elements, have emerged as remarkable biomaterials for use in bone regeneration. The effects of RE NMs on osteogenesis, such as promoting the osteogenic differentiation of mesenchymal stem cells, have been investigated. However, the contributions of the properties of RE NMs to bone regeneration and their interactions with various cell types during osteogenesis have not been reviewed. Here, we review the crucial roles of the physicochemical and biological properties of RE NMs and focus on their osteogenic mechanisms. RE NMs directly promote the proliferation, adhesion, migration, and osteogenic differentiation of mesenchymal stem cells. They also increase collagen secretion and mineralization to accelerate osteogenesis. Furthermore, RE NMs inhibit osteoclast formation and regulate the immune environment by modulating macrophages and promote angiogenesis by inducing hypoxia in endothelial cells. These effects create a microenvironment that is conducive to bone formation. This review will help researchers overcome current limitations to take full advantage of the osteogenic benefits of RE NMs and will suggest a potential approach for further osteogenesis research. Graphical abstract

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

Bone remodeling is an essential, delicately balanced physiological process of coordinated activity of bone cells that remove and deposit new bone tissue in the adult skeleton. Due to the complex nature of this process, many mathematical models of bone remodeling have been developed. Each of these models has unique features, but they have underlying patterns. In this review, the authors highlight the important aspects frequently found in mathematical models for bone remodeling and discuss how and why these aspects are included when considering the physiology of the bone basic multicellular unit, which is the term used for the collection of cells responsible for bone remodeling. The review also emphasizes the view of bone remodeling from a systems biology perspective. Understanding the systemic mechanisms involved in remodeling will help provide information on bone pathology associated with aging, endocrine disorders, cancers, and inflammatory conditions and enhance systems pharmacology. Furthermore, some features of the bone remodeling cycle and interactions with other organ systems that have not yet been modeled mathematically are discussed as promising future directions in the field. [ABSTRACT FROM AUTHOR]

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

Rare earth nanomaterials (RE NMs), which are based on rare earth elements, have emerged as remarkable biomaterials for use in bone regeneration. The effects of RE NMs on osteogenesis, such as promoting the osteogenic differentiation of mesenchymal stem cells, have been investigated. However, the contributions of the properties of RE NMs to bone regeneration and their interactions with various cell types during osteogenesis have not been reviewed. Here, we review the crucial roles of the physicochemical and biological properties of RE NMs and focus on their osteogenic mechanisms. RE NMs directly promote the proliferation, adhesion, migration, and osteogenic differentiation of mesenchymal stem cells. They also increase collagen secretion and mineralization to accelerate osteogenesis. Furthermore, RE NMs inhibit osteoclast formation and regulate the immune environment by modulating macrophages and promote angiogenesis by inducing hypoxia in endothelial cells. These effects create a microenvironment that is conducive to bone formation. This review will help researchers overcome current limitations to take full advantage of the osteogenic benefits of RE NMs and will suggest a potential approach for further osteogenesis research. [ABSTRACT FROM AUTHOR]

Bone fracture repair is a complex, multi-step process that involves communication between immune and stromal cells to coordinate the repair and regeneration of damaged tissue. In the US, 10% of all bone fractures do not heal properly without intervention, resulting in non-union. Complications from non-union fractures are physically and financially debilitating. We now appreciate the important role that immune cells play in tissue repair, and the necessity of the inflammatory response in initiating healing after skeletal trauma. The temporal dynamics of immune and stromal cell populations have been well characterized across the stages of fracture healing. Recent studies have begun to untangle the intricate mechanisms driving the immune response during normal or atypical, delayed healing. Various in vivo models of fracture healing, including genetic knockouts, as well as in vitro models of the fracture callus, have been implemented to enable experimental manipulation of the heterogeneous cellular environment. The goals of this review are to (1): summarize our current understanding of immune cell involvement in fracture healing (2); describe state- of-the art approaches to study inflammatory cells in fracture healing, including computational and in vitro models; and (3) identify gaps in our knowledge concerning immune-stromal crosstalk during bone healing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The contributions of skeletal cells to the processes of B cell development in the bone marrow (BM) have not been completely described. The von-Hippel Lindau protein (VHL) plays a key role in cellular responses to hypoxia. Previous work showed that Dmp1-Cre;Vhl conditional knockout mice (VhlcKO), which deletes Vhl in subsets of mesenchymal stem cells, late osteoblasts and osteocytes, display dysregulated bone growth and reduction in B cells. Here, we investigated the mechanisms underlying the B cell defects using flow cytometry and high-resolution imaging. In the VhlcKO BM, B cell progenitors were increased in frequency and number, whereas Hardy Fractions B-F were decreased. VhlcKO Fractions B-C cells showed increased apoptosis and quiescence. Reciprocal BM chimeras confirmed a B cell-extrinsic source of the VhlcKO B cell defects. In support of this, VhlcKO BM supernatant contained reduced CXCL12 and elevated EPO levels. Intravital and ex vivo imaging revealed VhlcKO BM blood vessels with increased diameter, volume, and a diminished blood-BM barrier. Staining of VhlcKO B cells with an intracellular hypoxic marker indicated the natural existence of distinct B cell microenvironments that differ in local oxygen tensions and that the B cell developmental defects in VhlcKO BM are not initiated by hypoxia. Our studies identify novel mechanisms linking altered bone homeostasis with drastic BM microenvironmental changes that dysregulate B cell development.

Yi-Ming Gao,1 Yan Pei,1 Fei-Fei Zhao,2 Ling Wang1 1Department of Orthopedic Oncology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Ling Wang, Tel +86031188603682, Email wangling2016uw@126.comAbstract: Osteosarcoma is an extremely malignant tumor, and its pathogenesis is complex and remains incompletely understood. Most cases of osteosarcoma are accompanied by symptoms of bone loss or result in pathological fractures due to weakened bones. Enhancing the survival rate of osteosarcoma patients has proven to be a long-standing challenge. Numerous studies mentioned in this paper, including in-vitro, in-vivo, and in-situ studies have consistently indicated a close association between the symptoms of bone loss associated with osteosarcoma and the presence of osteoclasts. As the sole cells capable of bone resorption, osteoclasts participate in a malignant cycle within the osteosarcoma microenvironment. These cells interact with osteoblasts and osteosarcoma cells, secreting various factors that further influence these cells, disrupting bone homeostasis, and shifting the balance toward bone resorption, thereby promoting the onset and progression of osteosarcoma. Moreover, the interaction between osteoclasts and various other cells types, such as tumor-associated macrophages, myeloid-derived suppressor cells, DCs cells, T cells, and tumor-associated fibroblasts in the osteosarcoma microenvironment plays a crucial role in disease progression. Consequently, understanding the role of osteoclasts in osteosarcoma has sparked significant interest. This review primarily examines the physiological characteristics and functional mechanisms of osteoclasts in osteosarcoma, and briefly discusses potential therapies targeting osteoclasts for osteosarcoma treatment. These studies provide fresh ideas and directions for future research on the treatment of osteosarcoma.Keywords: osteosarcoma, osteoclasts, bone remodeling, osteoimmunology, bone microenvironment

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. [ABSTRACT FROM AUTHOR]

In the bone immune microenvironment, immune cells can regulate osteoblasts through a complex communication network. Macrophages play a central role in mediating immune osteogenesis, exosomes derived from them have osteogenic regulation and can be used as carriers in bone tissue engineering. However, there are problems with exosomal therapy alone, such as poor targeting, and the content of loaded molecules cannot reach the therapeutic concentration. In this study, macrophage-derived exosomes modified with miR-365-2-5p were developed to accelerate bone healing. MC3T3-E1 cells were incubated with the culture supernatants of M0, M1 and M2 macrophages, and it was found that the culture medium of M2 macrophages had the most significant effects in contributing to osteogenesis. High-throughput sequencing identified that miR-365-2-5p was significantly expressed in exosomes derived from M2 macrophages. We incubated MC3T3-E1 with exosomes overexpressing or knocking down miR-365-2-5p to examine the biological function of exosome miR-365-2-5p on MC3T3-E1 differentiation. These findings suggested that miR-365-2-5p secreted by exosomes increased the osteogenesis of MC3T3-E1. Moreover, miR-365-2-5p had a direct influence over osteogenesis for MC3T3-E1. Sequencing analysis combined with dual luciferase detection indicated that miR-365-2-5p binded to the 3'-UTR of OLFML1. In summary, exosomes secreted by M2 macrophages targeted OLFML1 through miR-365-2-5p to facilitate osteogenesis. [ABSTRACT FROM AUTHOR]

Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP- multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants. [ABSTRACT FROM AUTHOR]

Background: Single-cell RNA sequencing (scRNA-seq) enables specific analysis of cell populations at single-cell resolution; however, there is still a lack of singlecell-level studies to characterize the dynamic and complex interactions between osteoporotic vertebral compression fractures (OVCFs) and Kümmell’s disease (KD) in the osteoimmune microenvironment. In this study, we used scRNA-seq analysis to investigate the osteoimmune microenvironment and cellular composition in OVCFs and KD. Methods: ScRNA-seq was used to perform analysis of fractured vertebral bone tissues from one OVCF and one KD patients, and a total of 8,741 single cells were captured for single-cell transcriptomic analysis. The cellularity of human vertebral bone tissue was further analyzed using uniform manifold approximation and projection. Pseudo-time analysis and gene enrichment analysis revealed the biological function of cell fate and its counterparts. CellphoneDB was used to identify the interactions between bone cells and immune cells in the osteoimmune microenvironment of human vertebral bone tissue and their potential functions. Results: A cellular profile of the osteoimmune microenvironment of human vertebral bone tissue was established, including mesenchymal stem cells (MSCs), pericytes, myofibroblasts, fibroblasts, chondrocytes, endothelial cells (ECs), granulocytes, monocytes, T cells, B cells, plasma cells, mast cells, and early erythrocytes. MSCs play an immunoregulatory function and mediate osteogenic differentiation and cell proliferation. The differentiation trajectory of osteoclasts in human vertebral bone tissue was also revealed. In addition, ECs actively participate in inflammatory infiltration and coupling with bone cells. T and B cells actively participate in regulating bone homeostasis. Finally, by identifying the interaction of ligand–receptor pairs, we found that immune cells and osteoclasts have bidirectional regulatory characteristics, have the effects of regulating bone resorption by osteoclasts and promoting bone formation, and are essential for bone homeostasis. It is also highlighted that CD8-TEM cells and osteoclasts might crosstalk via CD160–TNFRSF14 ligand–receptor interaction. Conclusion: Our analysis reveals a differential landscape of molecular pathways, population composition, and cell–cell interactions during OVCF development into KD. OVCFs exhibit a higher osteogenic differentiation capacity, owing to abundant immune cells. Conversely, KD results in greater bone resorption than bone formation due to depletion of MSCs and a relatively suppressed immune system, and this immune imbalance eventually leads to vertebral avascular necrosis. The site of action between immune cells and osteoclasts is expected to be a new therapeutic target, and these results may accelerate mechanistic and functional studies of osteoimmune cell types and specific gene action in vertebral avascular necrosis and pathological bone loss diseases, paving the way for drug discovery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Spinal fusion is important for the clinical success of patients undergoing surgery, and the immune system plays an increasingly recognized role. Osteoimmunology is the study of the interactions between the immune system and bone. Inflammation impacts the osteogenic, osteoconductive, and osteoinductive properties of bone grafts and substitutes and ultimately influences the success of spinal fusion. Macrophages have emerged as important cells for coordinating the immune response following spinal fusion surgery, and macrophage-derived cytokines impact each phase of bone graft healing. This review explores the cellular and molecular immune processes that regulate bone homeostasis and healing during spinal fusion. [ABSTRACT FROM AUTHOR]

Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost-/-) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost-/- chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost-/- BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM.

Bone fracture repair is a complex, multi-step process that involves communication between immune and stromal cells to coordinate the repair and regeneration of damaged tissue. In the US, 10% of all bone fractures do not heal properly without intervention, resulting in non-union. Complications from non-union fractures are physically and financially debilitating. We now appreciate the important role that immune cells play in tissue repair, and the necessity of the inflammatory response in initiating healing after skeletal trauma. The temporal dynamics of immune and stromal cell populations have been well characterized across the stages of fracture healing. Recent studies have begun to untangle the intricate mechanisms driving the immune response during normal or atypical, delayed healing. Various in vivo models of fracture healing, including genetic knockouts, as well as in vitro models of the fracture callus, have been implemented to enable experimental manipulation of the heterogeneous cellular environment. The goals of this review are to (1): summarize our current understanding of immune cell involvement in fracture healing (2); describe state-of-the art approaches to study inflammatory cells in fracture healing, including computational and in vitro models; and (3) identify gaps in our knowledge concerning immune-stromal crosstalk during bone healing.

Classically, particle-induced periprosthetic osteolysis at the implant–bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP− multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.

IntroductionDenosumab is a monoclonal antibody blocking the receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand (RANK/RANKL) pathway, thus inhibiting osteoclastogenesis. Since RANK and RANKL are also involved in the immune system activation, denosumab might interfere with the response against infections. Our study aimed to explore the relationship between denosumab treatment and coronavirus disease 2019 (COVID-19).Design and methodsThe occurrence and severity of COVID-19 were recorded in consecutive patients referred to the Endocrinology Department of Papa Giovanni XXIII Hospital, Bergamo, from 1 January 2020 to 1 January 2021. Patients treated with denosumab were compared to outpatient controls. Patients’ features were summarized by descriptive statistics. Multivariate logistic regression assessed the relationship between denosumab and COVID-19, adjusting for potential confounders. Subgroup analyses according to age, sex, body mass index (BMI), smoking status, and vitamin D levels were performed.ResultsThe final population included 331 patients treated with denosumab and 357 controls. COVID-19 incidence was lower in the denosumab group (7.6% vs. 14.6%, p = 0.004). COVID-19 severity was similar in both groups. Multiple logistic regression confirmed an association between denosumab and a reduced occurrence of symptomatic COVID-19 [odds ratio (OR) 0.46, 95% CI 0.21–0.98, p = 0.049]. Subgroup analyses suggested a potential protective effect of denosumab in patients over 75 years (OR 0.12, 95% CI 0.02–0.6, p = 0.011), with a significant interaction between denosumab and age categories (p = 0.047).ConclusionOur study confirms that denosumab may be safely continued in COVID-19 patients. RANK/RANKL inhibition seems associated with a reduced incidence of symptomatic COVID-19, particularly among the elderly.

Exosomes are natural extracellular vesicles that play a key role in inter- and intracellular communication. Currently they are considered as a promising therapeutic strategy for the treatment of various diseases. In osteoimmunology, exosomes can serve as biomarkers of bone homeostasis disorders and, at the same time, promising therapeutic agents with high stability in the biological environment, low immunogenicity and good bioavailability. In this review, we attempted to examine exosomes as natural mediators of intercellular communication, playing an essential role in the interaction of the immune system and bone tissue, based on an analysis of the PubMed database up to October 2023.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13, we demonstrate that lipopolysaccharides (LPS) from gram‐negative bacteria exacerbate NHO development in a toll‐like receptor‐4 (TLR4)‐dependent manner, signaling through the TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response‐88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI‐induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro‐adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case–control retrospective study in patients with traumatic brain injuries, infections with gram‐negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram‐negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammatory arthritis, such as rheumatoid arthritis (RA) and spondyloarthritis (SpA), often have a significant impact on bone tissue, where bone is not just a passive target but actively contributes to the disease progression. This review explores the pathogenic mechanisms involving bone, highlighting the complex molecular interactions between bone cells and the immune system, a field known as osteoimmunology. It discusses the unique processes of bone erosion and systemic bone loss in RA and SpA, as well as abnormal bone formation in SpA. Several rheumatologic diseases are primarily distinguished by their involvement of bone tissue, which not only serves as a mere target of the condition but often plays a pivotal role in its pathogenesis. This scenario is particularly prominent in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Given the immunological and systemic nature of these diseases, in this review, we report an overview of the pathogenic mechanisms underlying specific bone involvement, focusing on the complex interactions that occur between bone tissue's own cells and the molecular and cellular actors of the immune system, a recent and fascinating field of interest defined as osteoimmunology. Specifically, we comprehensively elaborate on the distinct pathogenic mechanisms of bone erosion seen in both rheumatoid arthritis and spondyloarthritis, as well as the characteristic process of aberrant bone formation observed in spondyloarthritis. Lastly, chronic inflammatory arthritis leads to systemic bone involvement, resulting in systemic bone loss and consequent osteoporosis, along with increased skeletal fragility. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA. [ABSTRACT FROM AUTHOR]

To investigate the relationship between individual postvaccination immune responses and subsequent risk of total hip arthroplasty (THA) due to idiopathic osteoarthritis (OA) or rheumatoid arthritis (RA). Results of tuberculin skin tests (TSTs) following the Bacille Calmette–Guerin (BCG) vaccination were used as a marker of individual immune responses. TST results from the mandatory mass tuberculosis screening program 1948–1975 (n = 236 770) were linked with information on subsequent THA during 1987–2020 from the Norwegian Arthroplasty Register. The multivariable Cox proportional hazard regression was performed. A total of 10 698 individuals received a THA during follow-up. In men, there was no association between TST and risk of THA due to OA (Hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92–1.12 for positive versus negative TST and HR 1.06, 95% CI 0.95–1.18 for strong positive vs negative TST), while the risk estimates increased with increasingly restrictive sensitivity analyses. In women, there was no association with THA due to OA for positive versus negative TST (HR 0.98, 95% CI 0.92–1.05), while a strong positive TST was associated with reduced risk of THA (HR 0.90, 95% CI 0.84–0.97). No significant associations were observed in the sensitivity analysis for women or for THA due to RA. Our results suggest that an increased postvaccination immune response is associated with a nonsignificant trend of increased risk of THA among men and a decreased risk among women, although risk estimates were small. [ABSTRACT FROM AUTHOR]

The elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an up-regulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages remaining within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C + CCR2hi monocytes, and S100a8hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of ‘osteoimmune-smart’ biomaterials in the bone regeneration field.

With the advances in understanding the relationships among biomaterials, the immune system and the skeletal system, the host responses elicited by implanted biomaterials can be balanced by properly designing material characteristics from the perspective of osteoimmunology. The immunoregulatory properties of bone tissue engineering scaffolds provide advantages for inducing macrophages from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype and promoting osseointegration. Hydrogels are increasingly a focus in bone tissue engineering, and the immune response can be affected by different compositions of hydrogels, such as the sources, concentration, molecular weight, coupling with fibronectin, and the addition of cross-linking agents. Different physicochemical properties of modified hydrogels can trigger different host immune responses, modified by using soft photolithography to fabricate micropatterned hydrogels, adding enzyme-sensitive sequences, ester bonds and dynamic covalent chemistry to prevent rapid or slow degradation of the hydrogels, and adding porogens and 3D printing to modify the hydrogels with macroporous interconnective pore structures, soft and injectable hydrogels, etc. These optimized hydrogels can reduce proinflammatory factors, promote M2 macrophage polarization, and minimize foreign body reactions to evoke bone regeneration. However, the mechanism underlying the bone immune response is still poorly understood, and further study of the effects of hydrogels with different physicochemical properties on immune regulation is needed.

Bioactive mesoporous glass nanospheres (nanoMBGs) charged with antiosteoporotic drugs have great potential for the treatment of osteoporosis and fracture prevention. In this scenario, cells of the immune system are essential both in the development of disease and in their potential to stimulate therapeutic effects. In the present work, we hypothesize that nanoMBGs loaded with ipriflavone can exert a positive osteoimmune effect. With this objective, we assessed the effects of non-loaded and ipriflavone-loaded nanoparticles (nanoMBGs and nanoMBG-IPs, respectively) on CD4+ Th2 lymphocytes because this kind of cell is implicated in the inhibition of osseous loss by reducing the RANKL/OPG relationship through the secretion of cytokines. The results indicate that nanoMBGs enter efficiently in CD4+ Th2 lymphocytes, mainly through phagocytosis and clathrin-dependent mechanisms, without affecting the function of these T cells or inducing inflammatory mediators or oxidative stress, thus maintaining the reparative Th2 phenotype. Furthermore, the incorporation of the anti-osteoporotic drug ipriflavone reduces the potential unwanted inflammatory response by decreasing the presence of ROS and stimulating intracellular anti-inflammatory cytokine release like IL-4. These results evidenced that nanoMBG loaded with ipriflavone exerts a positive osteoimmune effect. [ABSTRACT FROM AUTHOR]

Osteoporosis is a bone disease characterized by structural deterioration and low bone mass, leading to fractures and significant health complications. In this review, we summarize the mechanisms by which B-lymphocytes and neutrophils contribute to the development of osteoporosis and potential therapeutics targeting these immune mediators to reduce the proinflammatory milieu. B-lymphocytes—typically appreciated for their canonical role in adaptive, humoral immunity—have emerged as critical regulators of bone remodeling. B-lymphocytes communicate with osteoclasts and osteoblasts through various cytokines, including IL-7, RANK, and OPG. In inflammatory conditions, B-lymphocytes promote osteoclast activation and differentiation. However, B-lymphocytes also possess immunomodulatory properties, with regulatory B-lymphocytes (Bregs) secreting TGF-β1 to restrain pathogenic osteoclastogenesis. Neutrophils, the body's most prevalent leukocyte, also contribute to the proinflammatory environment that leads to osteoporotic bone remodeling. In aged individuals, neutrophils display reduced chemotaxis, phagocytosis, and apoptosis. Understanding the delicate interplay between B-lymphocytes and neutrophils in the context of impaired bone metabolism is crucial for targeted therapies for osteoporosis. [ABSTRACT FROM AUTHOR]

Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional Rankl deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, Rankl deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastrointestinal diseases in poultry are more significant because of high economic loss due to production loss, reduced feed efficiency, mortality, compromising bird welfare, and sometimes zoonotic importance. With the removal of antibiotic growth promoters in the diet, gastrointestinal disease incidences have grown in recent years. Gastrointestinal diseases have been shown to affect bone growth negatively; however, possible mechanisms have yet to be confirmed in chickens. Bone serves as a multifunctional organ in avian species, giving structural integrity to the body, aiding locomotion and flight, regulating mineral homeostasis, and supplementing calcium for eggshell formation. Furthermore, immune cells originate and reside in the bone marrow, sharing a milieu with bone cells, indicating a potential interaction in functions. In avian species, the prevalence of gastrointestinal diseases can alter the growth and the immune response, which costs a great fortune to the poultry industry. Previous studies have shown that coccidiosis and necrotic enteritis can dramatically reduce bone quality as well. However, possible mechanisms on how bone quality is influenced by these disease conditions have not yet been completely understood, other than the reduced feed intake. On the other hand, several mediators of the immune response, such as chemokines and cytokines, play a vital role in the differentiation and activation of osteoclasts responsible for bone resorption and osteoblasts for bone formation. In the case of Eimeria spp./Clostridium perfringens coinfection, these mediators are upregulated. One possible mechanism for accelerated bone loss after gastrointestinal illnesses might be immune-mediated osteoclastogenesis via cytokines-RANKL-mediated pathways. This review article thus focuses on osteoimmunological pathways and the interaction between host immune responses and bone biology in gastrointestinal diseases like coccidiosis and necrotic enteritis affecting skeletal health. [ABSTRACT FROM AUTHOR]

Bone defect repair is a common medical concern. In spite of various existing treatments, its management still requires improvement. Here we show that YAP, a downstream signaling of Hippo pathway, might interplay with redox oxygen species (ROS) and modulate osteoimmunology, which refers to the interaction between immune and skeletal system during bone defect repair. We modulated the ROS level of RAW264.7 cells and found YAP level was reversely regulated. Meanwhile, we detected the feedback of YAP on oxidation level. The results demonstrated that the antioxidant enzyme expression was in proportion to the YAP level of RAW264.7 cells. Additionally, indirect coculture system was applied and it indicated that RAW264.7 cells under oxidative stress could impede proliferation and migration ability of MC3T3-E1 pre-osteoblasts. Consistently, in vivo experiment verified high oxidant level slowed down mice osteogenesis during bone defect repair, while antioxidant and upregulation of YAP accelerated this process. Additionally, we established a mouse model with YAP conditional knockout in macrophages. The results identified that deficiency of YAP in macrophages negatively affected bone defect repair in vivo. In summary, our study indicated that ROS and YAP could jointly modulate osteogenesis via their effect on osteoimmunology. ABBREVIATIONS: GPX4, glutathione peroxidase 4; NAC, N-Acetyl-L-cysteine; qRT-PCR, real-time quantitative PCR; ROS, reactive oxygen species; Tb.N, trabecular number; Tb.Sp, trabecular separation. [ABSTRACT FROM AUTHOR]