Search

Tumor necrosis factor-alpha (TNF-α) is a significant cytokine that regulates bone resorption under inflammatory conditions. However, its mechanism of action in osteocytes remains unclear. In this study, highly purified osteocytes were isolated from dentin matrix protein 1 (DMP1)-Topaz mice using cell sorter. RNA sequencing (RNA-seq) revealed that TNF-α stimulation increased C-X-C motif chemokine ligand 10 (CXCL10) gene expression in osteocytes. Although CXCL10 did not affect osteoclast differentiation in vitro, it enhanced the migration of osteoclast precursors. Additionally, in the transwell co-culture system, TNF-α induced the migration of osteoclast precursors. However, this effect was attenuated by a CXCL10-neutralizing antibody. In vivo, mice were administered supracalvarial injections of TNF-α with or without the CXCL10-neutralizing antibody for 5 days. The percentage of CXCL10-positive osteocytes increased after TNF-α administration. Additionally, osteoclast formation and bone resorption were assessed. CXCL10-neutralizing antibody-treated calvariae exhibited a significantly lower number of osteoclasts and bone resorption than those treated with TNF-α alone. These results indicated that TNF-α-induced CXCL10, which affects the migration of osteocyte-derived osteoclast precursors, may enhance TNF-α-triggered osteoclast formation and bone resorption in vivo. [ABSTRACT FROM AUTHOR]

Glucose-insulinotropic polypeptide (GIP) is an incretin hormone that induces insulin secretion and decreases blood glucose levels. In addition, it has been reported to suppress osteoclast formation. Native GIP is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). (D-Ala2)GIP is a newly developed GIP analog that demonstrates enhanced resistance to DPP-4. This study aimed to evaluate the influence of (D-Ala2)GIP on osteoclast formation and bone resorption during lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro. In vivo, mice received supracalvarial injections of LPS with or without (D-Ala2)GIP for 5 days. Osteoclast formation and bone resorption were evaluated, and TNF-α and RANKL expression were measured. In vitro, the influence of (D-Ala2)GIP on RANKL- and TNF-α-induced osteoclastogenesis, LPS-triggered TNF-α expression in macrophages, and RANKL expression in osteoblasts were examined. Compared to the LPS-only group, calvariae co-administered LPS and (D-Ala2)GIP led to less osteoclast formation, lower bone resorption, and decreased TNF-α and RANKL expression. (D-Ala2)GIP inhibited osteoclastogenesis induced by RANKL and TNF-α and downregulated TNF-α expression in macrophages and RANKL expression in osteoblasts in vitro. Furthermore, (D-Ala2)GIP suppressed the MAPK signaling pathway. The results suggest that (D-Ala2)GIP dampened LPS-triggered osteoclast formation and bone resorption in vivo by reducing TNF-α and RANKL expression and directly inhibiting osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that exerts physiological effects via G protein-coupled receptor 120 (GPR120). In our previous studies, we figured out the inhibitory effects of DHA on TNF-α (Tumor necrosis factor-α)-induced osteoclastogenesis via GPR120 in vivo. Moreover, DHA directly suppressed RANKL expression in osteoblasts via GPR120 in vitro. In this study, we generated bone marrow chimeric mice using GPR120 deficient mice (GPR120-KO) to study the inhibitory effects of DHA on bone resorption and osteoclast formation. Bone marrow cells of wild-type (WT) or GPR120-KO mice were transplanted into irradiated recipient mice, which were WT or GPR120 deficient mice. The resulting chimeric mice contained stromal cells from the recipient and bone marrow cells, including osteoclast precursors, from the donor. These chimeric mice were used to perform a series of histological and microfocus computed tomography (micro-CT) analyses after TNF-α injection for induction of osteoclast formation with or without DHA. Osteoclast number and bone resorption were found to be significantly increased in chimeric mice, which did not express GPR120 in stromal cells, compared to chimeric mice, which expressed GPR120 in stromal cells. DHA was also found to suppress specific signaling pathways. We summarized that DHA suppressed TNF-α-induced stromal-dependent osteoclast formation and bone resorption via GPR120. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that has a range of positive impacts on human health, including anti-inflammatory effects and inhibition of osteoclast formation via G-protein-coupled receptor 120 (GPR120). Orthodontic force was reported to induce tumor necrosis factor-a (TNF-α) expression, which activates osteoclast differentiation during orthodontic tooth movement (OTM). The aim of this study was to investigate the influence of DHA on TNF-α-induced osteoclast formation and OTM in vivo. We examined osteoclast formation and bone resorption within the calvaria of both wild-type (WT) and GPR120-deficient (GPR120-KO) mice injected with phosphate-buffered saline (PBS), TNF-α, TNF-α and DHA, or DHA. DHA inhibited TNF-α-induced osteoclast formation and bone resorption in WT mice but had no effect in GPR120-KO mice. OTM experiments were performed in mouse strains with or without regular injection of DHA, and the effects of DHA on osteoclast formation in the alveolar bones during OTM were examined. DHA also suppressed OTM in WT but not GPR120-KO mice. Our data showed that DHA suppresses TNF-α-induced osteoclastogenesis and bone resorption via GPR120. TNF-α has considerable significance in OTM, and therefore, DHA may also inhibit TNF-α-induced osteoclast formation and bone resorption in OTM. [ABSTRACT FROM AUTHOR]

Objectives. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used as a treatment for type 2 diabetes mellitus and have also recently been applied to enhance bone quality and density, and increase the expression of bone markers. This study aimed to investigate the effect of a DPP-4 inhibitor on orthodontic tooth movement (OTM) and related root resorption in a mouse model. Materials and Methods. Mice were randomly divided into three groups: those undergoing OTM with the addition of a DPP-4 inhibitor (30 μg), those undergoing OTM and receiving phosphate-buffered saline (PBS), and those without force loading (control group). OTM was achieved by means of a nickel–titanium closed coil spring that moved the first molar in a mesial direction for 12 days. The distance of OTM was measured using silicone impression. Maxillae were removed for histological analysis or real-time PCR analysis. Results. The distance of OTM and the number of osteoclasts were significantly decreased after administration of the DPP-4 inhibitor, which also significantly suppressed the number of odontoclasts and root resorption after OTM. Furthermore, the mRNA expression of tumour necrosis factor-α (TNF-α) and the receptor activator of nuclear factor kappa-B ligand (RANKL) were decreased in DPP-4 inhibitor-treated mice compared with those receiving PBS and control animals. Conclusion. The DPP-4 inhibitor inhibited tooth movement and associated root resorption by blocking the formation of osteoclasts and odontoclasts, respectively. It also appeared to inhibit osteoclastogenesis and odontoclastogenesis by suppressing the expression of TNF-α and/or RANKL. [ABSTRACT FROM AUTHOR]

C-X-C motif chemokine 12 (CXCL12) belongs to the family of CXC chemokines. Lipopolysaccharide (LPS) induces inflammation-induced osteoclastogenesis and bone resorption, and in recent years, stimulatory effects of CXCL12 on bone resorption have also been reported. In the present study, we investigated the effects of CXCL12 on LPS-induced osteoclastogenesis and bone resorption. LPS was administered with or without CXCL12 onto mouse calvariae by daily subcutaneous injection. Numbers of osteoclasts and bone resorption were significantly elevated in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. Moreover, receptor activator of NF-kB ligand (RANKL) and tumor necrosis factor-α (TNF-α) mRNA levels were higher in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. These in vitro results confirmed a direct stimulatory effect of CXCL12 on RANKL- and TNF-α-induced osteoclastogenesis. Furthermore, TNF-α and RANKL mRNA levels were elevated in macrophages and osteoblasts, respectively, co-treated in vitro with CXCL12 and LPS, in comparison with cells treated with LPS alone. Our results suggest that CXCL12 enhances LPS-induced osteoclastogenesis and bone resorption in vivo through a combination of increasing LPS-induced TNF-α production by macrophages, increasing RANKL production by osteoblasts, and direct enhancement of osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed. [ABSTRACT FROM AUTHOR]

Osteoporosis morphology is characterized by bone resorption and decreases in micro-architecture parameters. Anti-osteoporosis therapy targets osteoclasts because bone resorption is a unique function of osteoclasts. Anti-c-fms antibodies against the receptor for macrophage colony-stimulating factor (M-CSF) inhibit osteoclast formation and bone resorption in vitro and in vivo. However, the effect of anti-c-fms antibodies on bone resorption in ovariectomized (OVX) mice is unknown. In this study, we evaluated the effect of anti-c-fms antibodies on osteoclast formation and bone resorption in osteoblast–osteoclast precursor co-culture in vitro and in OVX mice. Osteoblast and osteoclast precursor co-cultures treated with anti-c-fms antibodies showed significantly inhibited osteoclast formation, while cultures without anti-c-fms antibody treatment showed osteoclast formation. However, anti-c-fms antibodies did not change the receptor activator of nuclear factor kappa-B ligand (RANKL) or osteoprotegrin (OPG) expression during osteoblast and osteoclast differentiation in vitro. These results indicate that anti-c-fms antibodies directly affected osteoclast formation from osteoclast precursors in co-culture. OVX mice were treated with intraperitoneal injections of anti-c-fms antibody. The trabecular bone structure of the femur was assessed by micro-computer tomography. The anti-c-fms antibody inhibited osteoclast formation and bone loss compared with PBS-treated OVX mice. These results indicate potential for the therapeutic application of anti-c-fms antibodies for postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption. In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption. Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption. It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation. RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss. TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation. Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation. These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption. In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation. [ABSTRACT FROM AUTHOR]

Highlights • DPP-4 inhibitor inhibited LPS-induced osteoclast formation and bone resorption. • DPP-4 inhibitor inhibited LPS-induced osteoclast-related cytokines in vivo. • DPP-4 inhibitor downregulated LPS-induced TNF-α production by macrophages in vivo. • DPP-4 inhibitor did not directly affect osteoclast formation. Abstract Objectives Dipeptidyl peptidase 4 (DPP-4) inhibition is a new therapeutic strategy for type 2 diabetic patients. DPP-4 has been reported to enhance inflammation. However, the effect of DPP-4 inhibition on inflammation remains unknown. Lipopolysaccharide (LPS) is a strong inducer of inflammation and osteoclast formation. In this study, we investigated in vivo effects of DPP-4 inhibition on LPS-induced osteoclast formation and bone resorption, as well as in vitro effects of DPP-4 inhibition on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. Methods LPS with or without a DPP-4 inhibitor was subcutaneously injected into mouse calvaria for 5 days. Histological sections of calvaria were stained for tartrate-resistant acid phosphatase, and osteoclast numbers were determined. The ratio of calvaria bone resorption was evaluated via microfocal computed tomography reconstruction images. Results Osteoclast number and bone resorption were significantly lower in mice that underwent LPS and DPP-4 inhibitor co-administration than in those that underwent LPS administration alone. Moreover, RANKL, TNF-α, and M-CSF expression was reduced in the LPS and DPP-4 inhibitor co-administration group. In vitro , there were no direct effects of DPP-4 inhibitor or DPP-4 on RANKL- and TNF-α-induced osteoclastogenesis, or on LPS-induced RANKL expression in stromal cells. Nevertheless, macrophages from LPS and DPP-4 inhibitor co-administered mice exhibited lower TNF-α expression than macrophages from LPS-only mice. Notably, TNF-α expression was not reduced in LPS and DPP-4 inhibitor co-treated macrophages in vitro , compared with macrophages treated with LPS alone. [ABSTRACT FROM AUTHOR]