Search

The rhizome of Drynaria fortunei (Kunze ex Mett.) J. Sm., which is known as "Golsebo" in Korea, traditionally has been used to heal various inflammatory conditions, including bone metabolism disorders. It relieves blood extravasation, stops bleeding, repairs broken bone tissue, treats bone fractures, and kills bacteria. In this study, we evaluated the modulatory effects of DFP on the differentiation of bone-marrow-derived macrophages into osteoclasts. We performed tartrate-resistant acid phosphatase assays using DFP (at different concentrations and molecular weights) to evaluate the degree of bone resorption in the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis of bone-marrow-derived macrophages. TRAP activity increased with increasing DFP concentrations (0–200 µg/mL). Additionally, DFP significantly inhibited RANKL-induced osteoclastogenesis and controlled RANKL-mediated overexpression of c-Fos and nuclear factor of activated T cells 1, thereby downregulating osteoclast-specific gene (Atp6v0d2, cathepsin K, and DC-STAMP) expression. DFP thus has potential as a nutraceutical candidate for treating bone loss diseases, including osteoporosis in postmenopausal women. [ABSTRACT FROM AUTHOR]

Osteoporosis is among the major contributors of pathologic fracture in postmenopausal women, which is caused by the bone metabolic disorder owing to the over-activation of osteoclasts. Inhibition of osteoclast differentiation and maturation has become a mainstream research interest in the prevention of osteoporosis. Isoliensinine (Iso) is a dibenzyl isoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-cancer activities. However, whether it can be used as a potential treatment for osteoporosis remains undiscovered. Here, we investigated whether Iso might suppress the differentiation of osteoclasts in vitro and in vivo to play an anti-osteoporosis role. Our results showed that Iso inhibits the formation of mature multinuclear osteoclasts induced by RANKL, the bone resorption, and the osteoclast-specific genes expression by blocking the nuclear translocation of NF-κB p65, and the effect was in a dosage-dependent way. Furthermore, we investigated the therapeutic effect of Iso on osteoporosis in ovariectomized (OVX) mice. We found that Iso attenuated bone loss in the OVX mice and significantly promoted BS, Conn. DN, Tb.Th, TB.N, and BV/TV Index. All in all, Iso showed a prominent effect of osteoclast inhibition, with great promise for treating osteoporosis. [ABSTRACT FROM AUTHOR]

It is a viable strategy to inhibit osteoclast differentiation for the treatment of osteolytic diseases such as osteoporosis, rheumatoid arthritis and tumor bone metastases. Here we assessed the effects of insulicolide A, a natural nitrobenzoyl sesquiterpenoid derived from marine fungus, on receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and its protective effects on LPS-induced osteolysis mice model in vivo. The results demonstrated that insulicolide A inhibited osteoclastogenesis from 1 μM in vitro. Insulicolide A could prevent c-Fos and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) nuclear translocation and attenuate the expression levels of osteoclast-related genes and DC-STAMP during RANKL-stimulated osteoclastogenesis but have no effects on NF-κB and MAPKs. Insulicolide A can also protect the mice from LPS-induced osteolysis. Our research provides the first evidence that insulicolide A may inhibit osteoclastogenesis both in vitro and in vivo , and indicates that it may have potential for the treatment of osteoclast-related diseases. [ABSTRACT FROM AUTHOR]

Objectives: The present study was designed to investigate the effects of microRNA‐21 (miR‐21) on orthodontic tooth movement. Methods: The orthodontic tooth movement model was established in C57BL/6 and miR‐21−/− mice with or without implantation of activated T cells. Histological and histomorphometrical analyses were performed by hematoxylin–eosin staining. Tartrate‐resistant acid phosphate staining was used to analyze the osteoclast numbers during tooth movement. Enzyme‐linked immunosorbent assay, reverse transcription polymerase chain reaction, and immunohistochemistry analysis were used to examine the expression of RANKL and OPG. Results: In miR‐21−/− mice, the distance of tooth movement was retarded, the osteoclast number was decreased, and serum RANKL expression was strongly reduced. MiR‐21 promoted the secretion of RANKL from activated T cells. Furthermore, activated T cells could partially rescue the decreased orthodontic tooth movement distance in miR‐21−/− mice. MiR‐21 was shown to promote orthodontic tooth movement by modulating the RANKL/OPG balance in T cells. Conclusions: The impact of miR‐21 on tooth movement was better elucidated, furthering our understanding of its role and clinical applications in orthodontics. [ABSTRACT FROM AUTHOR]

Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) are regulators of bone remodeling, but are also considered to play important roles in coronary artery disease (CAD). This study evaluated potential associations of soluble (s) RANKL and OPG with atherosclerosis-relevant cytokines. Blood was collected from 414 individuals who presented to our hospital with intermediate likelihood for CAD for further examination. Plasma concentrations of total sRANKL, OPG, and 20 cytokines were measured using sandwich-type enzyme-linked immunoassays (ELISAs; OPG and sRANKL) and Luminex laser-based fluorescence analysis and correlated with each other. The plasma levels of interferon-γ (IFN-γ) and the T-helper cell 2 cytokines interleukin-4 (IL-4) and IL-13 showed a positive correlation with sRANKL. The association with sRANKL levels was negative for IFN-γ-induced protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1). The strongest independent association with sRANKL in multivariable analyses was found for IFN-γ (positive) and IP-10 (negative), while IL-13 showed a positive and independent association with OPG plasma levels. OPG and sRANKL plasma levels correlate strongly and independently with specific circulating atherosclerosis-related cytokines in patients with intermediate cardiovascular risk. [ABSTRACT FROM AUTHOR]

Bone remodeling, a physiological process characterized by bone formation by osteoblasts and bone resorption by osteoclasts, is important for the maintenance of healthy bone in adult humans. Osteoclasts play a critical role in bone erosion and osteoporosis and are bone-specific multinucleated cells generated through differentiation of monocyte/macrophage lineage precursors. Receptor activator of NF-κB ligand (RANKL) has been reported to induce osteoclast differentiation. In this study, we explored whether Gracilaria verrucosa extracts (GE) could affect RANKL-mediated osteoclast differentiation. GE significantly inhibited RANKL-activated osteoclast differentiation by inhibiting protein expression of c-fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), vital factors in RANKL-mediated osteoclastogenesis. In addition, GE attenuated ovariectomy-induced bone loss in mice. In summary, GE can prevent osteoclastogenesis and hormone-related bone loss via blockage of c-fos-NFATc1 signaling. Our results suggest that GE may have therapeutic potential in the treatment of postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Background Osteoarthritis (OA) is a major health problem in the increasingly elderly population. Therefore, it is crucial to prevent and treat OA at an early stage. The present study investigated whether pamidronate disodium (PAM), a bone-loss inhibitor, can significantly prevent or reverse the progression of early anterior cruciate ligament transection (ACLT)- induced OA. Whether therapeutic intervention is associated with regulation of the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), metalloproteinase-9 (MMP-9) or Toll-like receptor-4 (TLR-4) in cartilage and/or subchondral bone was also investigated. Methods 60 New Zealand rabbits were randomized into four groups: Sham-operated (n =20); ACLT (n =20); short-term treatment with PAM (PAM-S, n =10) and long-term treatment with PAM (PAM-L, n =10). For cartilage and subchondral bone testing, rabbits from Sham and ACLT groups were harvested at 2, 4, 6, and 14 weeks. Rabbits were given PAM from the 4th week after ACLT operation in PAM-S and PAM-L group, and were harvested at 6 and 14 weeks, respectively. Trabecular characteristics and cartilage changes were detected using Micro-CT, safranin O and rapid green staining, respectively. Immunohistochemical staining for OPG and RANKL were also performed. OPG, RANKL, MMP-9 and TLR-4 expression was evaluated by western blot analysis. Results Micro-CT and histology analyses indicated that PAM treatment for 2 or 10 weeks could completely prevent or reverse osteoarthritic subchondral bone loss and cartilage surface erosion. Immunohistochemistry and western blot analysis indicated that expression of OPG and RANKL increased, although RANKL expression increased more significantly than that of OPG. Therefore the ratio of OPG to RANKL was lower in the ACLT group. However, the ratio of OPG to RANKL in the PAM group was significantly higher than that in the ACLT group. Additionally, expression of MMP-9 and TLR-4 were upregulated in the ACLT group and downregulated in the PAM treated groups. Conclusions PAM can significantly inhibit and even reverse early osteoarthritic subchondral bone loss, thus alleviating the process of cartilaginous degeneration. The mechanisms involved may be associated with the upregulation of OPG expression, and downregulation of RANKL, MMP- 9 and TLR-4 expression. [ABSTRACT FROM AUTHOR]

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal-related events (SREs) that cause significant morbidity. Bone destruction in myeloma is due to an increased activity of osteoclasts coupled with suppressed bone formation by osteoblasts. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease. Zoledronic acid and pamidronate have shown similar efficacy in reducing SREs in a randomized study in the conventional chemotherapy era. However, in a recent study (the Myeloma-IX trial of the UK Medical Research Council, MRC), zoledronic acid was found to be superior to clodronate in reducing SREs, but also it produced a survival advantage of approximately 10 months in patients with bone disease at baseline. During recent years, novel agents targeting bone have been used in myeloma. This review focuses on the established therapy of myeloma bone disease and also on recent advances in treatment that take advantage of the better understanding of the pathophysiology of bone disease. [ABSTRACT FROM AUTHOR]

Booij-Vrieling HE, Ferbus D, Tryfonidou MA, Riemers FM, Penning LC, Berdal A, Everts V, Hazewinkel HAW. Increased vitamin D-driven signalling and expression of the vitamin D receptor, MSX2, and RANKL in tooth resorption in cats. Eur J Oral Sci 2010; 118: 39–46. © 2010 The Authors. Journal compilation© 2010 Eur J Oral Sci Tooth resorption occurs in 20–75% of cats ( Felis catus). The aetiology is not known, but vitamin D is suggested to be involved. Vitamin D acts through a nuclear receptor (VDR) and increases the expression of receptor activator of nuclear factor-κB ligand ( rankl) and muscle segment homeobox 2 ( msx2) genes. Mice lacking the muscle segment homeobox 2 ( msx2) gene show decreased levels of rankl, suggesting an interaction among VDR, MSX2, and RANKL. Here, we investigated the expression of VDR, MSX2, and RANKL proteins, and the activity of the VDR-mediated signalling pathway (using the quantitative polymerase chain reaction on VDR target genes), in tooth resorption, and measured the serum levels of vitamin D metabolites in cats. Tooth resorption was categorized into either resorptive or reparative stages. In the resorptive stage, odontoclasts expressed MSX2 and RANKL (100% and 88%, respectively) and fibroblasts expressed VDR and MSX2 (both at 100%), whereas fibroblasts expressed RANKL in only 29% of the sites analysed. In the reparative stage, cementoblasts expressed VDR, MSX2, and RANKL, whereas fibroblasts expressed VDR and MSX2, but not RANKL. The vitamin D status did not differ between the groups, based on the serum levels of 25-hydroxycholecalciferol. However, increased expression of VDR protein, and the relative gene expression levels of 1α-hydroxylase and the VDR-target gene, 24-hydroxylase, indicated the involvement of an active vitamin D signalling in the pathophysiology of tooth resorption in cats. [ABSTRACT FROM AUTHOR]

Background and Objective: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. However, little is known about how nicotine influences the expression of osteolytic mediators in cigarette smoking-associated periodontal diseases. The aim of this study was to investigate the expression of interleukin-1, interleukin-8, receptor activator of nuclear factor-κB ligand (RANKL), gelatinases and tissue-type plasminogen activator in U2OS cells (from the human osteosarcoma cell line) stimulated with nicotine. Material and Methods: Differences in the expression of interleukin-1, interleukin-8 and RANKL mRNAs, in response to exposure to various concentrations of nicotine (0, 0.125, 0.25, 0.5 and 1 mm) were evaluated in U2OS cells using the reverse transcripttion–polymerase chain reaction.In addition, the levels of interleukin-1, interleukin-8 and RANKL proteins were determined using enzyme-linked immunosorbent assays. The gelatinolytic and caseinolytic activities in nicotine treated-U2OS cells were demonstrated using gelatin and casein zymography, respectively. Results: Nicotine was found to increase the expression of interleukin-1, interleukin-8 and RANKL mRNA and protein in U2OS cells ( p < 0.05). The gelatin zymograms revealed that matrix metalloproteinase (MMP)-2 and MMP-9 were secreted by U2OS cells. The secretion of MMP-2 and MMP-9 occurred in a dose-dependent manner that was dependent on the concentration of nicotine ( p < 0.05). Casein zymography exhibited a caseinolytic band with a molecular weight of 70 kDa, indicative of the presence of tissue-type plasminogen activator. Tissue-type plasminogen activator was also found to be up-regulated by nicotine in a dose-dependent manner ( p < 0.05). Conclusion: Taken together, the results of the present study indicated that smoking modulation of bone destruction in periodontal disease may involve various osteolytic mediators, such as interleukin-1, interleukin-8, RANKL, MMP-2, MMP-9, and tissue-type plasminogen activator. [ABSTRACT FROM AUTHOR]

Background and Objective: Inflammatory immune reactions that occur in response to periodontopathogens are thought to protect the host against infection, but may trigger periodontal destruction. However, the molecular and genetic mechanisms underlying host susceptibility to periodontal infection and to periodontitis development have still not been established in detail. Material and Methods: In this study, we examined the mechanisms that modulate the outcome of Aggregatibacter (Actinobacillus) actinomycetemcomitans-induced periodontal disease in mice mouse strains selected for maximal (AIRmax) or minimal (AIRmin) inflammatory reactions. Results: Our results showed that AIRmax mice developed a more severe periodontitis than AIRmin mice in response to A. actinomycetemcomitans infection, and this periodontitis was characterized by increased alveolar bone loss and inflammatory cell migration to periodontal tissues. In addition, enzyme-linked immunosorbent assays demonstrated that the levels of the cytokines interleukin-1β, tumor necrosis factor-α and interleukin-17 were higher in AIRmax mice, as were the levels of matrix metalloproteinase (MMP)-2, MMP-13 and receptor activator of nuclear factor-κB ligand (RANKL) mRNA levels. However, the more intense inflammatory immune reaction raised by the AIRmax strain, in spite of the higher levels of antimicrobial mediators myeloperoxidase and inducible nitric oxide synthase, did not enhance the protective immunity to A. actinomycetemcomitans infection, because both AIRmax and AIRmin strains presented similar bacterial loads in periodontal tissues. In addition, the AIRmax strain presented a trend towards higher levels of serum C-reactive protein during the course of disease. Conclusion: Our results demonstrate that the intensity of the inflammatory immune reaction is associated with the severity of experimental periodontitis, but not with the control of A. actinomycetemcomitans periodontal infection, suggesting that the occurrence of hyperinflammatory genotypes may not be an evolutionary advantage in the complex host–pathogen interaction observed in periodontal diseases. [ABSTRACT FROM AUTHOR]

Recent years brought the discovery of new members of TNF receptor superfamily - osteoprotegerin/receptor activator of nuclear factor-κB and its ligand (OPG/RANK/RANKL) system as regulator of bone remodeling. Further studies showed its involvement in control of vascular and immune system. Animal studies' results confirm the OPG/RANK/RANKL role in pathogenesis of vascular calcifications and osteoporosis. Human studies, especially in patients with chronic kidney disease (CKD), have brought many conflicting data. Understanding of exact contribution of each molecule creating this axis may be crucial for diagnosis and treatment of CKD complications involving renal osteodystrophy and vascular calcification. In this review we try to summarize recent knowledge and OPG/RANK/RANKL role in patient with chronic kidney diseases. [ABSTRACT FROM AUTHOR]

RAW 264.7 macrophage cells differentiate into osteoclast-like cells in the presence of RANKL. Participation of M-CSF in RANKL-induced osteoclast formation of RAW 264.7 cells was examined. TRAP-positive osteoclast-like cells appeared in RAW 264.7 cells cultured in the presence of RANKL. RANKL-induced osteoclast formation was markedly inhibited by anti-M-CSF antibody. RANKL augmented M-CSF mRNA expression and M-CSF production in RAW 264.7 cells. Further, anti-M-CSF antibody inhibited the expression of RANK, c-fms, c-fos and TRAP mRNA in RANKL-stimulated RAW 264.7 cells. However, anti-M-CSF antibody did not affect the expression of DC-STAMP in the stimulated cells. Therefore, RANKL was suggested to induce osteoclast formation in RAW 264.7 cells via augmented production of M-CSF. The putative role of M-CSF in RANKL-induced osteoclast formation of RAW 264.7 cells is discussed. [ABSTRACT FROM AUTHOR]

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. β2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.Leukemia (2005) 19, 1969–1976. doi:10.1038/sj.leu.2403890; published online 4 August 2005 [ABSTRACT FROM AUTHOR]

Background: To clarify the roles of osteoclast regulatory factors in progression of odontogenic tumors, expression of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL), and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) were analyzed in ameloblastomas as well as tooth germs.Methods: Tissue specimens of nine tooth germs and 36 benign and one malignant ameloblastomas were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry for the expression of PTHrP, ODF/RANKL, and OCIF/OPG.Results: Expression of PTHrP, ODF/RANKL, and OCIF/OPG mRNA was detected in all tooth germ and ameloblastoma samples. Immunohistochemical reactivity for PTHrP was recognized in both normal and neoplastic odontogenic epithelial cells. In ameloblastomas, PTHrP reactivity in peripheral columnar or cuboidal cells was stronger than that in central polyhedral cells, and keratinizing cells showed increased PTHrP reactivity. ODF/RANKL and OCIF/OPG were expressed predominantly in mesenchymal cells rather than in odontogenic epithelial cells in both tooth germs and ameloblastomas. Epithelial ODF/RANKL and OCIF/OPG expression was slightly lower in ameloblastomas than in tooth germs. Tumor cells in plexiform ameloblastomas showed slightly higher reactivity for PTHrP and ODF/RANKL than tumor cells in follicular ameloblastomas.Conclusion: Expression of PTHrP, ODF/RANKL and OCIF/OPG in tooth germs and ameloblastomas suggests that these factors might locally regulate bone metabolism and dynamics in tooth development as well as in progression of ameloblastomas. These factors might also be involved in tumor cell differentiation and/or tumor tissue structuring in ameloblastomas. [ABSTRACT FROM AUTHOR]

Denosumab–Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to denosumab. A 43-year-old female was referred to the Endocrinology, Diabetes & Metabolism Department for treatment of low bone mineral density (BMD) following endocrine therapy with letrozole and lucrin because of breast cancer. She developed premature menopause at the age of 36 years when she underwent a left lumpectomy due to an infiltrating duct carcinoma of the breast (T1 NO MO) and was subsequently started on endocrine therapy. Denosumab was started to prevent osteoporosis. On the third year after starting on denosumab and one month after she received the last injection, she became ill. The routine biochemical analysis showed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rose appreciatively to 10 times the upper limit of normal (ULN). The gamma-glutamyl transferase (GGT) level was elevated slightly to 67 U/L (0–38 U/L). The serum gamma-globulin level was elevated to 1.72 g/dL (0.7–1.6 gr/dl), while the total bilirubin (TB) and serum albumin levels were normal. A liver biopsy revealed a moderate to severe chronic inflammatory infiltrate containing MUM-1 positive plasma cells. In addition, numerous CD-3 positive small T lymphocytes and few CD-20 positive B lymphocytes and eosinophils were seen in the portal tracts. Moderate to severe interface hepatitis, bile duct proliferation and mild portal fibrosis were also identified. The results could be consistent with the diagnosis of drug-induced liver injury (DILI). [ABSTRACT FROM AUTHOR]