OBJECTIVES: Osteoporosis is a disease of bones that is thought to result from an imbalance between bone resorption and bone formation. Although osteoporosis itself has no symptoms, osteoporosis caused by osteoclasts leads to an increased risk of fracture. Here we examined the effects of cornus officinalis on receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclast differentiation. METHODS: We evaluated the effects of cornus officinalis on RANKL-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs) and performed a cytotoxicity assay, reverse transcriptase-polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS: Cornus officinalis significantly inhibits RANKL-mediated osteoclast differentiation in a dose-dependent manner, but without cytotoxicity against BMMs. The mRNA expression of tartrate-resistant acid phosphatase (TRAP), osteoclast-associated receptor (OSCAR), c-Fos, and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) in BMMs treated with RANKL was considerably inhibited by cornus officinalis treatment. Also, cornus officinalis inhibits the protein expression of c-Fos and NFATc1. Cornus officinalis greatly inhibits RANKL-induced phosphorylation of p38 and c-JUN N-terminal kinase (JNK). Also, cornus officinalis significantly suppresses RANKL-induced degradation of I-kappaB. CONCLUSIONS: Taken together, our results suggest that cornus officinalis may be a useful the treatment of osteoporosis.
Acid Phosphatase ; Blotting, Western ; Bone Resorption ; Cornus ; Cytoplasm ; Isoenzymes ; JNK Mitogen-Activated Protein Kinases ; Macrophages ; Osteoclasts ; Osteogenesis ; Osteoporosis ; Phosphorylation ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; RNA, Messenger ; T-Lymphocytes

OBJECTIVES: Osteoclast differentiation and bone resorption are considered a potential therapeutic target to the treatment of erosive bone diseases, including osteoporosis and rheumatoid arthritis. Poria cocos Wolf (PCW), commonly used herbal medicine, has previously been reported to induce anti-inflammatory effect and anti-cancer effect, and to modulate immunologic responses. However, the effects of PCW on osteoclasts, and its detailed mechanisms are not proven. Therefore, we examined the inhibitory mechanism of PCW on osteoclast differentiation and bone resorption. MATERIALS AND METHODS: To analyze the effects of PCW on osteoclast differentiation, we examined osteoclast differentiation in bone marrow macrophages (BMMs) treated with or without of PCW by TRAP staining. The expression of c-Fos, NFATc1, TRAP and OSCAR mRNA was determined by RT-PCR and the protein levels of c-Fos, NFATc1, p38, ERK, JNK, Akt and IkappaB were assessed by western blot. Also, we evaluated the effect of PCW on bone resorption using hydroxyapatite plate. RESULTS: PCW significantly inhibited RANKL-mediated osteoclast differentiation without any evidence of cytotoxicity. We founded that PCW strongly inhibited RANKL-induced osteoclast formation when added during the early stage of cultures, suggesting that PCW acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, PCW inhibited the phosphorylation of p38 and JNK, also inhibited RANKL-induced expression of c-Fos, NFATc1, TRAP and OSCAR. In addition, PCW suppressed the bone resorption of mature osteoclasts. CONCLUSIONS: These findings suggest that PCW may be a potential novel drug for bone disorders by targeting the differentiation of osteoclasts as well as their functions.
Arthritis, Rheumatoid ; Blotting, Western ; Bone Diseases ; Bone Marrow ; Bone Resorption ; Cocos ; Durapatite ; Herbal Medicine ; Macrophages ; Osteoclasts ; Osteoporosis ; Phosphorylation ; Poria ; RNA, Messenger ; Wolves

It is important to identify therapeutic compounds with no adverse effects for use in the chemotherapy of patients with bone-related diseases. The aim of this study was to identify a new compound that inhibits osteoclast differentiation and bone resorption. Herein, we examined the effects of 1',2'-dihydrorotenone on osteoclast differentiation and bone resorption in vitro and in vivo. 1',2'-dihydrorotenone inhibited receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation of cultured bone marrow macrophages (BMMs) in a dose-dependent manner. However, 1',2'-dihydrorotenone did not exert cytotoxic effect on BMMs. 1',2'-dihydrorotenone suppressed the expression of c-fos and NFATc1 as well as osteoclast-specific genes in BMMs treated with RANKL. Treatment with RANKL inhibited the expression of inhibitors of differentiation/DNA binding (Id)1, 2, and 3; however, in the presence of 1',2'-dihydrorotenone, RANKL did not suppress the expression of Id1, 2, and 3. Furthermore, 1',2'-dihydrorotenone inhibited bone resorption and considerably attenuated the erosion of trabecular bone induced by lipopolysaccharide treatment. Taken together, these results suggest that 1',2'-dihydrorotenone has the potential to be applied in therapies for bone-related diseases.
Bone Marrow ; Bone Resorption ; Humans ; Macrophages ; Osteoclasts ; Receptor Activator of Nuclear Factor-kappa B ; Rotenone

Among the several rotenoids, amorphigenin is isolated from the leaves of Amopha Fruticosa and it is known that has anti-proliferative effects and anti-cnacer effects in many cell types. The main aim of this study was to investigate the effects of amorphigenin on osteoclast differentiation in vitro and on LPS treated inflammatory bone loss model in vivo. We show here that amorphigenin inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages in a dose dependent manner without cellular toxicity. Anti-osteoclastogenic properties of amorphigenin were based on a down-regulation of c-fos and NFATc1. Amorphigenin markedly inhibited RANKL-induced p38 and NF-kappaB pathways, but other pathways were not affected. Micro-CT analysis of the femurs showed that amorphigenin protected the LPS-induced bone loss. We concluded that amorphigenin can prevent inflammation-induced bone loss. Thus we expect that amorphigenin could be a treatment option for bone erosion caused by inflammation.
Bone Marrow ; Down-Regulation ; Femur ; Inflammation ; Macrophages ; NF-kappa B ; Osteoclasts ; Osteoporosis ; Rotenone ; T-Lymphocytes

Balance between bone-resorbing osteoclats and bone-forming osteoblasts is important in bone homeostasis. In particular, increased osteoclast formation and activity are responsible for bone diseases such as osteoporosis, rheumatoid arthritis, periodontal disease. Natural metabolites of plants have recently received much attention as lead compounds for the development of novel therapeutic strategy. The purpose of this study was to search the natural products to inhibition osteoclast differentiation. Water extract of papaya significantly inhibited receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in a dose dependent manner. However, water extract of papaya did not affect cytotoxicity when compared with control. Water extract of papaya inhibited the phosphorylation of p38 and JNK induced by RANKL. The mRNA expression of c-Fos, NFATcl, TRAP and OSCAR induced by RANKL was inhibited by water extract of papaya treatment. Also, water extract of papaya suppressed the protein expression of c-Fos and NFATc1 in BMMs treated with RANKL. Taken together, these results suggest that papaya may be a useful drug in the treatment of bone-related disease.
Arthritis, Rheumatoid ; Biological Agents ; Bone Diseases ; Bone Marrow ; Carica ; Homeostasis ; Macrophages ; Osteoblasts ; Osteoclasts ; Osteoporosis ; Periodontal Diseases ; Phosphorylation ; RANK Ligand ; RNA, Messenger ; Water

PURPOSE: This study was undertaken to investigate the effect of a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, FR167653, on urinary albumin excretion and on the expression of slit diaphragm-associated proteins in diabetic rats. METHODS: Thirty-two Sprague-Dawley rats were injected with diluent [control (C), N=16] or streptozotocin intraperitoneally (DM, N=16). Eight rats from each group were treated with 5 mg/kg/day FR 167653 (C+FR, DM+FR) for 6 weeks. At the time of sacrifice, 24-hour urinary albumin excretion was determined by ELISA. Glomerular nephrin, P-cadherin, and ZO-1 mRNA and protein expression were determined by real-time PCR and Western blot, respectively, with sieved glomeruli. RESULTS: Urinary albumin excretion was significantly higher in DM compared to C rats, and this increase in albuminuria was significantly inhibited by the administration of FR167653 in DM rats. Glomerular phospho-p38 MAPK protein expression was significantly increased in DM rats compared to C rats, and FR167653 treatment significantly attenuated the increase in phospho-p38 MAPK expression in DM glomeruli. Nephrin mRNA and protein expression were higher in 6-week DM compared to C glomeruli, and these increases were significantly abrogated with FR167653 treatment in DM rats. In contrast, FR167653 had no effects on the decrease in P-cadherin expression and the increase in ZO-1 expression observed in DM glomeruli. CONCLUSION: These findings suggest that FR167653, a p38 MAPK inhibitor, reduce the amount of albuminuria in early diabetic nephropathy, and this anti-proteinuric effect seems to be related with the change of glomerular nephrin expression.
Albuminuria ; Animals ; Blotting, Western ; Cadherins ; Diabetic Nephropathies ; Enzyme-Linked Immunosorbent Assay ; Membrane Proteins ; p38 Mitogen-Activated Protein Kinases ; Protein Kinases ; Proteins ; Pyrazoles ; Pyridines ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Streptozocin

Posttransplant lymphoproliferative disorder (PTLD) is an uncommon but life-threatening complication of immunosuppressive therapy following solid organ transplantation. It encompasses a heterogeneous group of lymphoproliferative disorders ranging from reactive, polyclonal hyperplasia to aggressive non- Hodgkin's lymphoma. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV) infection. Gastrointestinal involvement, especially small bowel and colon, is common in patients with PTLD, but the duodenum is rarely involved. We have experienced a case of PTLD involving the duodenum eight years after kidney transplantation in 50-year-old man. Two weeks before admission, he had complained of epigastric pain, and was diagnosed as pangastritis and duodenal ulcer by upper gastrointestinal endoscopy. He was admitted due to aggravated epigastric pain despite anti-ulcer medication. On the seventh hospital day, we found a new mass-like lesion in the pyloric area of antrum and diffuse ulceration in the duodenum by follow-up endoscopy. Histologic findings revealed diffuse large B-cell lymphoma. During reduction in immunosuppressive regimens, his conditions deteriorated rapidly. He died of sepsis associated with duodenal ulcer perforation, 18 days after diagnosis.
B-Lymphocytes ; Colon ; Diagnosis ; Duodenal Ulcer ; Duodenum* ; Endoscopy ; Endoscopy, Gastrointestinal ; Follow-Up Studies ; Herpesvirus 4, Human ; Hodgkin Disease ; Humans ; Hyperplasia ; Kidney Transplantation* ; Kidney* ; Lymphoma, B-Cell ; Lymphoproliferative Disorders* ; Middle Aged ; Organ Transplantation ; Sepsis ; Transplants ; Ulcer

PURPOSE: The aims of this retrospective study were to evaluate the sequential changes of parathyroid hormone (iPTH) and calcium metabolism after renal transplantation (RTP) and to identify risk factors for hypertension (HPT). METHODS: Biochemical bone parameters were reviewed in 264 patients at pre-transplant, 6, 12, 36 and 60 months after RTP. RESULTS: iPTH levels fell significantly during the first six months after RTP and remained substantially stable thereafter. The mean total serum calcium level showed significant increase during the first six months and progressive and significant decline after the first year. The mean serum phosphorus level returned to the normal range during the first six months and remained normal thereafter. The serum alkaline phosphatase (ALP) level increased during the first year and gradually decreased after then. The prevalence of persistent HPT was 17.8%. Patients with persistent HPT had significantly elevated serum levels of iPTH at the time of RTP and had spent a longer time on dialysis. Significant positive correlations were observed between the serum iPTH levels on the one hand and the pre-transplant iPTH, serum ALP, and creatinine levels on the other hand. CONCLUSION: The prevalence of persistent HPT after RTP is not uncommon. The patients with long duration of dialysis showing high serum level of iPTH at the time of transplantation are at risk for persistent HPT.
Alkaline Phosphatase ; Calcium ; Creatinine ; Dialysis ; Hand ; Humans ; Hyperparathyroidism, Secondary ; Hypertension ; Kidney Transplantation* ; Metabolism* ; Parathyroid Hormone* ; Phosphorus ; Prevalence ; Reference Values ; Retrospective Studies ; Risk Factors

Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule that mediates cell proliferation, differentiation, migration, and angiogenesis in vivo. However, the roles of S1P on pathogenesis of arthritis have been not completely understood. This study was designed to determine the effects of S1P modulation on collageninduced arthritis (CIA) model. DBA/1J mice were injected with collagen into the tail for induction of CIA model. S1P was administered into the peritoneal cavity every other days from day 1 to day 42 after collagen injection. To determine the degree of damage in CIA, we examined macroscopic findings of CIA. The inflammation and bone destruction of CIA mice were evaluated by histo-patholigy and radiography (CT and microradiography). The expressions of TNF-alpha, IL-6, and RANKL which have important roles in pathogenesis of rheumatoid arthritis and bone destruction were observed by immuno-histochemical staining. After injection with collagen in the DBA/1J mice, CIA was induced by swelling in the knee and ankle joint. Administration of S1P suppressed damages and incidence of arthritis elicited by collagen. In histologic and radiographic studies, S1P strongly suppressed the infiltration of inflammatory cells, the swelling of synovial membrane, erosion, and the destruction of bone on CIA mice. Injection of S1P resulted in down-regulation of the expression of the pro-inflammatory and bone destruction mediators such as TNF-alpha, IL-6, and RANKL on CIA mice. Furthermore, S1P suppressed the differentiation of bone marrow cells into osteoclasts by RANKL. In conclusion, this study suggest that S1P has protective effects on inflammation and bone destruction during pathogenesis of CIA, which indicates S1P can be a new possible therapeutic strategy for rheumatoid arthritis
Animals ; Ankle Joint ; Arthritis ; Arthritis, Rheumatoid* ; Bone Marrow Cells ; Cell Proliferation ; Collagen ; Down-Regulation ; Incidence ; Inflammation* ; Interleukin-6 ; Knee ; Mice* ; Osteoclasts ; Peritoneal Cavity ; Radiography ; Sphingosine ; Synovial Membrane ; Tail ; Tumor Necrosis Factor-alpha

PURPOSE: We examined the clinical characteristics and incidence of adults idiopathic nephrotic syndrome (NS) according to pathologic diagnosis, age, sex. METHODS: We retrospectively reviewed the clinical and pathological characteristics of primary glomerular lesions in adults idiopathic NS taken a renal biopsy from 1978 to 2005 at the Dongsan Medical Center. We compared the prevalence of adults idiopathic NS according to the pathologic diagnosis between two time intervals 1978 to 1990 and 1991 to 2005. RESULTS: The patients had mean age of 36.7+/-16.3 years and male to female ratio was 1.7:1 with male predominance. The frequency of histopathologic diagnoses were minimal change nephrotic syndrome (MCNS) 51.6%, membranous glomerulonephritis (MGN) 21.3%, focal segmental glomerulosclerosis (FSGS) 12.1%, IgA nephropathy 9.1%, membranoproliferative glomerulonephritis (MPGN) 4.2% in decreasing order of frequency. The mean age was youngest in MCNS (32.9+/-15.1) and oldest in MGN (46.2+/-16.6). Between 1978 to 1990 period and 1991 to 2005 period, the prevalence of MGN was significantly increased, whereas the prevalence of MPGN was decreased significantly. The prevalence of MCNS had a tendency to decrease and that of IgA nephropathy had a tendency to increase, however, both didn't reach statistical significance. The incidence of FSGS didn't show a significant change during the both study periods. CONCLUSION: MCNS was the most common disease among adults idiopathic NS. MGN was the most frequent etiology in patients older than 45 years. The incidence of MGN was increased over the 28-year period, and that of MPGN decreased significantly. There was no change in the frequency of FSGS.
Adult* ; Biopsy ; Diagnosis ; Female ; Glomerulonephritis, IGA ; Glomerulonephritis, Membranoproliferative ; Glomerulonephritis, Membranous ; Glomerulosclerosis, Focal Segmental ; Humans ; Incidence ; Korea* ; Male ; Nephrosis, Lipoid ; Nephrotic Syndrome* ; Prevalence ; Retrospective Studies