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Regulation of TNF Expression and Transcription A, RAW-C3 cells were treated with vehicle (Cont), TSH (200 ng/ml), a mixture of IL-1 (10 ng/ml) and TNF (50 ng/ml), or a mixture of IL-1 (10 ng/ml) and TNF (50 ng/ml) in the presence or absence of TSH (200 ng/ml) for 6 h, and TNF mRNA expression was examined. Levels of TNF expression were compared between treated and control groups (*, P 0.05) or between IL-1/TNF and IL-1/TNF plus TSH treatments ( †, P 0.05). B, TNF mRNA expression as measured by PCR-based run-on assay. RAW-C3 cells were treated as described above and as detailed in Materials and Methods. Nuclear fractions incubated without rNT were used as negative controls, and TNF expression levels are described as a ratio to controls; *, P 0.05. C, The effects of cytokines and hormones on TNF transcription were examined in stably transfected RAW-C3 cells expressing 176 bp-Luc. Cells were treated with vehicle, RANKL (100 ng/ml), or a mixture of IL-1 (10 ng/ml) and TNF (50 ng/ml) in the presence or absence of TSH (200 ng/ml). Luciferase activity was measured after 6 h for all samples except the RANKL-treated sample, which was measured after 12 h. Luciferase activity was compared between treated and control groups (*, P 0.05) and between treated groups in the absence or presence of TSH ( †, P 0.05). D, The 5-deletion constructs of the TNF promoter (from 0, 67, 137, 148, 157, 176, 197, 228, 485, or 685 bp to 115 bp) with luciferase were transiently transfected into RAW-C3 cells and treated with either vehicle or RANKL (100 ng/ml) for 12 h and luciferase activity measured. The results shown here were replicated at least twice. Luciferase activity was compared between control and RANKL-treated groups (*, P 0.05).
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We have previously shown that mice lacking the TSH receptor (TSHR) exhibit osteoporosis due to enhanced osteoclast formation. The fact that this enhancement is not observed in double-null mice of TSHR and TNFalpha suggests that TNFalpha overexpression in osteoclast progenitors (macrophages) may be involved. It is unknown how TNFalpha expression is...
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... have previously reported that the increase in os- teoclast formation seen in TSHR / mice is due to TNF overexpression in osteoclast progenitors and that IL-1/TNF, as well as RANKL directly increases TNF expression (5). Figure 1A shows that IL-1/TNF treatment increases TNF expression in RAW-C3 cells. This increase is significantly reduced in the pres- ence of TSH, suggesting that TSH is indeed negatively regulating the levels of cytokines known to be involved in osteoporosis. ...
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... further examine whether the ef- fects of IL-1/TNF and TSH on TNF expression are due to the regulation of TNF transcription, we per- formed a PCR-based run-on assay and a luciferase promoter assay. Figure 1B clearly shows that TNF transcriptional activity, as measured by the PCR- based run-on assay, increased 2-fold in cultures of RAW-C3 cells after IL-1/TNF treatment, but that this increase was ameliorated by the presence of TSH. This result further suggests that TSH is attenuating the effect of IL-1/TNF. ...
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... than in either treated or untreated samples incubated with rNT. Treatment with RANKL (100 ng/ml) and IL-1/TNF (a mixture of 10 ng/ml IL-1 and 50 ng/ml TNF) significantly increased luciferase activity in RAW-C3 cells stably transfected with the TNF promoter-luciferase construct (176 bp-Luc), but this activity was attenuated by TSH treat- ment (Fig. 1C). This result indicates that TNF expres- sion is indeed regulated at the transcriptional level by cytokines (RANKL and IL-1/TNF) and at least one hormone (TSH). Unless otherwise described, we used the same doses of RANKL (100 ng/ml) and IL-1/TNF (a mixture of 10 ng/ml IL-1 and 50 ng/ml TNF) in all experiments using RAW-C3 ...
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... roles of these proteins have been inade- quately studied in macrophages. We therefore exam- ined murine TNF transcriptional regulation in detail using 5-deletion constructs of the TNF promoter coupled to the luciferase reporter gene pGL3 in RAW-C3 cells. Cells were stimulated for 12 h with or without RANKL, and luciferase activity was measured (Fig. 1D). The basal activity of the TNF promoter begins from 137 bp, peaks at 148 bp, and declines by 157 bp. We found that RANKL treatment specif- ically enhanced the promoter activity of the 148 bp- Luc construct. These data suggest that RANKL-re- sponsive sequence (RRS) in the TNF promoter is located between 157 and 137 bp (CCG AGA CAG AGG ...
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... GATA, and CREB consensus sequences did not (Fig. 2C). In addition, mutation analysis indicated the sequence downstream of the 12th nucleotide (AGG TGT AGG GCC) between 148 and 137 bp on the RRS was required for protein binding (Fig. 2D). Interestingly, this sequence was identical to the one that exhibited a sharp in- crease in luciferase activity (Fig. ...
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... TNF expression in osteoclast progenitors. The fact that these mice de- velop osteoporosis (5) suggests that TNF overpro- duction may play a major role in the development of this condition. Here we used a promoter assay and a PCR-based run-on assay to show that TSH directly down-regulates TNF transcription induced by IL-1/ TNF or RANKL treatment (Fig. 1). Our results further support the idea that TSH is a key regulator of TNF transcriptional activity and possibly of other down- stream events in osteoclastogenesis and bone ...
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... an attempt to define the regulatory mechanism responsible for endogenous TNF overexpression, we performed a deletion analysis of the murine TNF pro- moter ( Fig. 1D) followed by the EMSA to identify im- portant binding protein(s). We show that the TNF promoter contains a RRS required for the RANKL- induced increase in expression of a TNF promoter- luciferase construct (Fig. 1D). Mutations in the RRS ameliorate protein binding from the crude nuclear frac- tion (Fig. 2D), and TSH inhibits TNF ...
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... regulatory mechanism responsible for endogenous TNF overexpression, we performed a deletion analysis of the murine TNF pro- moter ( Fig. 1D) followed by the EMSA to identify im- portant binding protein(s). We show that the TNF promoter contains a RRS required for the RANKL- induced increase in expression of a TNF promoter- luciferase construct (Fig. 1D). Mutations in the RRS ameliorate protein binding from the crude nuclear frac- tion (Fig. 2D), and TSH inhibits TNF transcriptional activity through the RRS (Fig. 2B). We next used a RRS-bound streptavidin gel affinity column and mass spectroscopy to identify HMGB1 and HMGB2 as RRS-binding proteins (Figs. 3D and 6, B and C). The fact ...
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... It has been shown in vivo that HMGB2 forms a multiprotein complex with HSC70, GRP58, and GAPD. Influence on resistance to chemotherapeutic drugs in cancer patients, in particular, in ovarian cancer [75,[113][114][115]. ...
... The nuclear complex of HMGB1, HMGB2, HSC70, GRP58, and GAPD alters DNA conformation [75,[113][114][115]. ...
... HMGB1/2 and TNF play a critical role in the regulation of osteoclastogenesis and bone remodeling [59,110,111,115]. ...
High-Mobility Group (HMG) chromosomal proteins are the most numerous nuclear non-histone proteins. HMGB domain proteins are the most abundant and well-studied HMG proteins. They are involved in variety of biological processes. HMGB1 and HMGB2 were the first members of HMGB-family to be discovered and are found in all studied eukaryotes. Despite the high degree of homology, HMGB1 and HMGB2 proteins differ from each other both in structure and functions. In contrast to HMGB2, there is a large pool of works devoted to the HMGB1 protein whose structure–function properties have been described in detail in our previous review in 2020. In this review, we attempted to bring together diverse data about the structure and functions of the HMGB2 protein. The review also describes post-translational modifications of the HMGB2 protein and its role in the development of a number of diseases. Particular attention is paid to its interaction with various targets, including DNA and protein partners. The influence of the level of HMGB2 expression on various processes associated with cell differentiation and aging and its ability to mediate the differentiation of embryonic and adult stem cells are also discussed.
... The TSH receptor, although expressed mainly on the basolateral membrane of thyroid follicular cells, is expressed in both osteoblasts and osteoclasts (46). It has been shown to bind TSHR expressed on osteoclasts, inhibit osteoclast formation and survival and prevent bone resorption mainly by reducing local tumor necrosis factor-a production (47)(48)(49)(50), and also stimulate osteoblasts to accelerate bone formation (51,52), while directly affecting bone remodeling with a potential protective effect on bone. Several clinical studies have shown a positive correlation between serum TSH levels and BMD (53)(54)(55)(56) and a negative correlation with bone turnover index (57, 58), indicating that TSH may be an important protective factor against osteoporosis. ...
Thyroid-stimulating hormone (TSH) suppression therapy is one of the common treatments for most patients with differentiated thyroid cancer (DTC). Unfortunately, its detrimental effects on bone health are receiving increasing attention. It may increase the risk of osteoporosis and osteoporotic fractures. The trabecular bone score (TBS) is a relatively new gray-scale texture measurement parameter that reflects bone microarchitecture and bone strength and has been shown to independently predict fracture risk. We reviewed for the first time the scientific literature on the use of TBS in DTC patients on TSH suppression therapy and aim to analyze and compare the utility of TBS with bone mass strength (BMD) in the management of skeletal health and prediction of fracture risk. We screened a total of seven relevant publications, four of which were for postmenopausal female patients and three for all female patients. Overall, postmenopausal female patients with DTC had lower TBS and a significant reduction in TBS after receiving TSH suppression therapy, but their BMD did not appear to change significantly. In addition, TBS was also found to be an independent predictor of osteoporotic fracture risk in postmenopausal women with DTC receiving TSH suppression therapy. However, due to limitations in the number of studies and study populations, this evidence is not sufficient to fully demonstrate the adverse effects of TSH suppression therapy on patients’ TBS or BMD and the efficacy of TBS, and subsequent larger and more case-cohort studies are needed to further investigate the relationship and application of TBS to TSH suppression therapy in terms of skeletal health impairment and fracture risk in DTC patients.
... These findings are relevant to clinical observations, where patients with hyperthyroidism are accompanied by elevated TNFα and soluble TNF receptor (TNFR) levels [84]. Mechanistically, TSH inhibits high-mobility group box proteins (HMGB) 1 and 2 expression and their binding to DNA, and suppresses JNK1/2 and IĸBα phosphorylation and c-jun and p65 nuclear translocation, all of which are critical steps in TNFα synthesis [2,85]. Likewise, TSHR overexpression de-creases the activator protein (AP)-1 and nuclear factor κB (NFκB) binding in response to RANKL and TNFα/IL-1 [83]. ...
Over the past years, pituitary hormones and their receptors have been shown to have non-traditional actions that allow them to bypass the hypothalamus-pituitary-effector glands axis. Bone cells-osteoblasts and osteoclasts-express receptors for growth hormone, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin, and vasopressin. Independent skeletal actions of pituitary hormones on bone have been studied using genetically modified mice with haploinsufficiency and by activating or inactivating the receptors pharmacologically, without altering systemic effector hormone levels. On another front, the discovery of a TSH variant (TSH-βv) in immune cells in the bone marrow and skeletal action of FSHβ through tumor necrosis factor α provides new insights underscoring the integrated physiology of bone-immune-endocrine axis. Here we discuss the interaction of each pituitary hormone with bone and the potential it holds in understanding bone physiology and as a therapeutic target.
... Although HMGB1 is mostly considered to bind DNA non-specifically either by recognizing secondary structure of DNA molecules or its forms such as minicircles [58], there is potential evidence of a DNA-binding site specificity for HMGB1. It has been shown that HMGB1 upregulates TNFα gene via binding to the receptor activator for nuclear factor-kappa B ligand (RANKL)-responsive sequence (CCG AGA CAG AGG TGT AGG GCC), spanning from -157 to -137 bp of the 5'-flanking region of the TNFα gene [76]. Interestingly, this motif shares similarity of its 14-15 out of 21 nt fragment with the antisense strand (nt 731-710) of HBV genomes across genotype A-H. ...
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), serving as the viral persistence form and transcription template of HBV infection, hijacks host histone and non-histone proteins to form a minichromosome and utilizes posttranslational modifications (PTMs) "histone code" for its transcriptional regulation. HBV X protein (HBx) is known as a cccDNA transcription activator. In this study we established a dual system of the inducible reporter cell lines modelling infection with wildtype (wt) and HBx-null HBV, both secreting HA-tagged HBeAg as a semi-quantitative marker for cccDNA transcription. The cccDNA-bound histone PTM profiling of wt and HBx-null systems, using chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR), confirmed that HBx is essential for maintenance of cccDNA at transcriptionally active state, characterized by active histone PTM markers. Differential proteomics analysis of cccDNA minichromosome established in wt and HBx-null HBV cell lines revealed group-specific hits. One of the hits in HBx-deficient condition was a non-histone host DNA-binding protein high mobility group box 1 (HMGB1). Its elevated association to HBx-null cccDNA was validated by ChIP-qPCR assay in both the HBV stable cell lines and infection systems in vitro. Furthermore, experimental downregulation of HMGB1 in HBx-null HBV inducible and infection models resulted in transcriptional re-activation of the cccDNA minichromosome, accompanied by a switch of the cccDNA-associated histones to euchromatic state with activating histone PTMs landscape and subsequent upregulation of cccDNA transcription. Mechanistically, HBx interacts with HMGB1 and prevents its binding to cccDNA without affecting the steady state level of HMGB1. Taken together, our results suggest that HMGB1 is a novel host restriction factor of HBV cccDNA with epigenetic silencing mechanism, which can be counteracted by viral transcription activator HBx.
... There is a RANKL-responsive sequence in the 5′ flanking region of the TNFα gene, to which RANKL triggers the binding of high-mobility group box proteins (HMGB) 1 and 2-this binding is crucial for TNFα expression and osteoclastogenesis. TSH, in turn, downregulated HMGB1/2 expression and inhibits binding to HMGB1/2 to DNA, in addition to attenuating JNK1/2 and IĸBα phosphorylation and c-jun and p65 nuclear translocation (9,80). Likewise, TSHR overexpression decreases the AP-1 and nuclear factor-κB binding in response to RANKL and TNFα/IL-1 (77). ...
Thyrotropin, traditionally seen as a pituitary hormone that regulates thyroid glands, has additional roles in physiology including skeletal remodeling. Population-based observations in subjects with euthyroidism or subclinical hyperthyroidism indicated a negative association between bone mass and low-normalTSH. The findings of correlative studies were supported by small intervention trials using recombinant human TSH (rhTSH) injection, and genetic and case-based evidence. Genetically-modified mouse models, which disrupt the reciprocal relationship between TSH and thyroid hormone, have allowed us to examine an independent role of TSH. Since the first description of osteoporotic phenotype in haploinsufficient Tshr +/- mice with normal thyroid hormone levels, the anti–osteoclastic effect of TSH has been documented in in vitro and in vivo studies. Further studies showed that increased osteoclastogenesis in Tshr–deficient mice was mediated by TNFα. Low TSH not only increased osteoclastogenesis, but also decreased osteoblastogenesis in bone marrow–derived primary osteoblast cultures. However, later in vivo studies using small and intermittent dose of rhTSH showed pro-anabolic effect, which suggests that its action might be dose- and frequency-dependent. TSHR was shown to interact with IGF1R, and VEGF and Wnt pathway might play a role in TSH effect on osteoblasts. The expression and direct skeletal effect of a biologically active splice variant of TSHβ subunit (TSHβv) in bone-marrow-derived macrophage and other immune cells suggest local skeletal effect of TSHR. Further studies of how locally secreted TSHβv and systemic TSHβ interact in skeletal remodeling through the endocrine, immune and skeletal system will help us better understand the hyperthyroidism-induced bone disease.
... It also aids in identification of bacterial products, boosting the innate immune response [29]. Through binding to cellular receptors, such as toll-like receptor 4 (TLR4), TLR9, and RAGE, HMGB1 activates innate immune cells, endothelial cells to produce proinflammatory cytokines, chemokines, tissue factor or adhesion molecules [10,[29][30][31][32][33]. Furthermore, HMGB1 inhibits elimination through phagocytosis of apoptotic neutrophils, impeding resolution of inflammation [29]. ...
Cytokines are mediators of inflammation induced in the course of Clostridioides difficile infection (CDI). High Mobility Group Box 1 (HMGB1) is a cytokine playing an important role in the pathogenesis of numerous inflammatory and autoimmune diseases. The aim of the study was to assess the HMGB1 gene expression in the course of CDI. We have performed a prospective case-control study- including 55 adult patients, among them 27 with CDI, who were hospitalized from October 2018 to February 2020 and 28 healthy volunteers. We assessed: a complete blood count with differential leukocyte count, blood creatinine, albumin, and C-reactive protein (CRP) levels. Then, the expression of the HMGB1 gene was evaluated using quantitative Real-Time PCR. Patients with CDI were found to have a significant increase in white blood cells (WBC), neutrophil count, and CRP levels, they also exhibited decreased levels of albumin compared with controls. The HMGB1 gene expression was significantly lower among patients with CDI compared with the control group and significantly, inversely correlated with CRP level in blood. In conclusion, we have observed a decreased expression of the HMGB1 gene in peripheral blood of patients with mild or moderate CDI, which hypothetically could reflect their diminished capability to fight the pathogen.
... Moreover, other experiments showed that RANKL treatment stimulates the HMGB1 and HMGB2 proteins to bind the RANKL-responsive sequence and upregulates TNFα transcription. A direct correlation between the expression of HMGB and TNFα and osteoclast formation in TSHR-null mice and TNFα-null mice has also been proposed, thus concluding that HMGB and TNFα play critical roles in the regulation of osteoclastogenesis and the remodeling of bone [62]. ...
Alarmins are endogenous mediators released by cells following insults or cell death to alert the host's innate immune system of a situation of danger or harm. Many of these, such as high-mobility group box-1 and 2 (HMGB1, HMGB2) and S100 (calgranulin proteins), act through RAGE (receptor for advanced glycation end products), whereas the IL-1 and IL-33 cytokines bind the IL-1 receptors type I and II, and the cellular receptor ST2, respectively. The alarmin family and their signal pathways share many similarities of cellular and tissue localization, functions, and involvement in various physiological processes and inflammatory diseases including osteoporosis. The aim of the review was to evaluate the role of alarmins in osteoporosis. A bibliographic search of the published scientific literature regarding the role of alarmins in osteoporosis was organized independently by two researchers in the following scientific databases: Pubmed, Scopus, and Web of Science. The keywords used were combined as follows: “alarmins and osteoporosis”, “RAGE and osteoporosis”, “HMGB1 and osteoporosis”, “IL-1 and osteoporosis”, “IL 33 and osteopororsis”, “S100s protein and osteoporosis”. The information was summarized and organized in the present review. We highlight the emerging roles of alarmins in various bone remodeling processes involved in the onset and development of osteoporosis, as well as their potential role as biomarkers of osteoporosis severity and progression. Findings of the research suggest a potential use of alarmins as pharmacological targets in future therapeutic strategies aimed at preventing bone loss and fragility fractures induced by aging and inflammatory diseases.
... The receptor activator for NFκB ligand (RANKL) stimulates endogenous TNFα expression and it is necessary for osteoclast formation. Additionally, RANKL and a mixture with IL1 and TNFα increase osteoclastogenesis (59). Moreover, we showed that the TSHR null mice exhibit an elevated TNFα expression in osteoclast progenitors. ...
... Moreover, we showed that the TSHR null mice exhibit an elevated TNFα expression in osteoclast progenitors. The fact that these mice develop osteoporosis (43) suggests that TNFα overproduction may play a major role in the development of this condition since TSH has been shown to directly downregulate TNFα transcription induced by IL1 or RANKL treatments (59). ...
The dogma that thyroid-stimulating hormone (TSH) solely regulates the production of thyroid hormone from the thyroid gland has hampered research on its wider physiological roles. The action of pituitary TSH on the skeleton has now been well described; in particular, its action on osteoblasts and osteoclasts. It has also been recently discovered that the bone marrow microenvironment acts as an endocrine circuit with bone marrow-resident macrophages capable of producing a novel TSH-β subunit variant (TSH-βv), which may modulate skeletal physiology. Interestingly, the production of this TSH-βv is positively regulated by T3 accentuating such modulation in the presence of thyroid overactivity. Furthermore, a number of small molecule ligands acting as TSH agonists, which allosterically modulate the TSH receptor have been identified and may have similar modulatory influences on bone cells suggesting therapeutic potential. This review summarizes our current understanding of the role of TSH, TSH-β, TSH-βv, and small molecule agonists in bone physiology.
... This anti-osteoclastogenic action of TSH is mediated by reduced NF-κB and JNK signaling and TNFα production ( Abe et al. 2003;Hase et al. 2006). The effect of TSH on TNFα synthesis is mediated transcriptionally by binding of two high mobility group box proteins, HMGB1 and HMGB2, to TNFα gene promoter ( Yamoah et al. 2008). TNFα production is expectedly upregulated in osteoporotic TSHR −/− mice ( Abe et al. 2003), and the genetic deletion of TNFα in these mice reverses the osteoporosis, as well as the bone formation and resorption defects, proving that the TSHR −/− phenotype is mediated by TNFα, at least in part ( Hase et al. 2006;Sun et al. 2013). ...
A single specific function has been traditionally ascribed to each anterior and posterior pituitary glycoprotein hormone. However, it has become clear over the past decade that these hormones and their receptors have more ubiquitous functions. Organs, such as the skeleton, are regulated by and respond to pituitary hormones, particularly when circulating levels are perturbed in disease. Additionally, certain pituitary hormones are also expressed in bone cells, underscoring paracrine regulation.
... Hypoxia might cause the release of HMGB1 145 . HMGB1 enhances the activity of tissue plasminogen activator and MMPs, and activates osteoclastogenesis, thereby leading to destruction of cartilage and bone 159,160 . ...
Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy). In OA, high mobility group protein B1 (HMGB1) and S100 proteins, along with many other alarmins, are abundantly secreted by joint cells, promoting cartilage matrix catabolism, osteophyte formation, angiogenesis and hypertrophic differentiation. The involvement of alarmins in chronic inflammatory arthritides is suggested by their presence in serum at high levels in these conditions, and their expression within inflamed synovia and synovial fluid. S100 proteins, HMGB1, IL-33 and other endogenous molecules have deleterious effects on joints, and can recruit immune cells such as dendritic cells to inflamed synovia, initiating the adaptive immune response and perpetuating disease. Improving our understanding of the pathological mechanisms associated with these danger signals is important to enable the targeting of new therapeutic approaches for arthritis.
