Bone remodeling and bone regeneration are essential for preserving skeletal integrity and maintaining mineral homeostasis. T cells, as key members of adaptive immunity, play a pivotal role in bone remodeling and bone regeneration by producing a range of cytokines and growth factors. In the physiological state, T cells are involved in the maintenance of bone homeostasis through interactions with mesenchymal stem cells, osteoblasts, and osteoclasts. In pathological states, T cells participate in the pathological process of different types of osteoporosis through interaction with estrogen, glucocorticoids, and parathyroid hormone. During fracture healing for post-injury repair, T cells play different roles during the inflammatory hematoma phase, the bone callus formation phase and the bone remodeling phase. Targeting T cells thus emerges as a potential strategy for regulating bone homeostasis. This article reviews the research progress on related mechanisms of T cells immunity involved in bone remodeling and bone regeneration, with a view to providing a scientific basis for targeting T cells to regulate bone remodeling and bone regeneration.
骨重建和骨再生对于保持骨骼完整性和维持矿物质稳态至关重要。T淋巴细胞为适应性免疫的关键成员，通过产生一系列细胞因子和生长因子，在骨重建和骨再生过程中起着举足轻重的作用。在生理状态下，T淋巴细胞通过与间充质干细胞、成骨细胞、破骨细胞的交互作用参与骨稳态的维持；在病理状态下，T淋巴细胞通过与雌激素、糖皮质激素、甲状旁腺激素的协作参与不同类型骨质疏松的病理过程；在损伤后修复的骨折愈合过程中，T淋巴细胞在炎症血肿期、骨痂形成期和骨重建期发挥了不同的作用。因此，靶向T淋巴细胞成为调节骨稳态的潜在策略。本文综述了T细胞免疫参与骨重建和骨再生的研究进展及相关机制，以期为靶向T淋巴细胞调控骨重建和骨再生提供科学依据。.

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

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

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.

The parasitic worm-derived immunomodulator, ES-62 rescues defective levels of IL-10-producing regulatory B cells (Bregs) and suppresses chronic Th1/Th17-driven inflammation to protect against joint destruction in the mouse collagen-induced arthritis (CIA) model of rheumatoid arthritis. Such autoimmune arthritis is also associated with dysbiosis of the gut microbiota and disruption of intestinal barrier integrity. We recently further exploited the CIA model to show that ES-62\'s prevention of joint destruction is associated with protection of intestinal barrier integrity and normalization of the gut microbiota, thereby suppressing the gut pathology that precedes the onset of autoimmunity and joint damage in CIA-mice. As the status of the gut microbiota impacts on immune responses by influencing haematopoiesis, we have therefore investigated whether ES-62 harnesses the homeostatic mechanisms regulating this gut-bone marrow (BM) axis to resolve the chronic inflammation promoting autoimmunity and joint destruction in CIA. Reflecting this, ES-62 was found to counteract the BM myeloid/lymphoid bias typically associated with chronic inflammation and infection. This was achieved primarily by ES-62 acting to maintain the levels of lymphoid lineages (B220+ and CD3+ cells) observed in naïve, healthy mice but lost from the BM of CIA-mice. Moreover, ES-62\'s ability to prevent bone-destroying osteoclastogenesis was found to be associated with its suppression of CIA-induced upregulation of osteoclast progenitors (OCPs) in the BM. Critically, and supporting ES-62\'s targeting of the gut-BM axis, this rewiring of inflammatory haematopoiesis was lost in mice with a depleted microbiome. Underlining the importance of ES-62\'s actions in restoring steady-state haematopoiesis, the BM levels of B and T lymphoid cells were shown to be inversely correlated, whilst the levels of OCPs positively correlated, with the severity of joint damage in CIA-mice.

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.

Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages\' memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette-Guérin (BCG) to induce a \'trained\' state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a \'tolerance\' state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine.

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.

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.