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Osteonecrosis of the femoral head （ONFH） is a painful and debilitating disease caused by impaired blood supply to the femoral head and cellular and tissue degeneration， leading to gradual destruction of the bone structure and progressive collapse of the femoral head. The main pathological mechanism of ONFH is the disruption of the balance between bone absorption and the reconstruction of new bone， resulting from microcirculation damage and decreased cellular tissue ability. This imbalance leads to biomechanical changes and accelerates the pathological progression of ONFH. In the early stages， clinical manifestations may not be obvious， mainly presenting as pain or discomfort in the hip or groin area， which can be relieved after rest. In the later stage of the disease， pain intensifies， and limb shortening， lower limb weakness， difficulty walking， or limping may occur. Currently， western medicine commonly uses osteogenic agents， anticoagulants， and artificial joint replacement for treatment， but there are also many issues such as prosthesis loosening and infection. Research has shown that traditional Chinese medicine （TCM） treatment of ONFH takes a holistic approach and employs multi-functional， multi-target， and multi-system Chinese medicine therapies， ensuring the safety and effectiveness of the treatment. The osteoprotegerin （OPG）/receptor activator of nuclear factor-κB （RANK）/RANK ligand （RANKL） signaling pathway plays a crucial role in maintaining the dynamic balance of bone remodeling. TCM treatments utilize this pathway to promote apoptosis of osteoclasts， reduce bone resorption， and accelerate bone formation， thereby playing an important role in the prevention and treatment of ONFH. This paper reviewed the role of OPG/RANK/RANKL signaling pathway and related cytokine expression in ONFH by reviewing relevant literature in China and abroad and research status of Chinese medicinal monomers， Chinese medicinal formulations， and combinations with physical therapy in increasing osteoblast secretion， promoting OPG expression， enhancing cytokine expression levels， and inhibiting osteoclast activity for the prevention and treatment of ONFH. This paper is expected to provide new ideas and directions for TCM in the prevention and treatment of ONFH.
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Abstract Duchenne muscular dystrophy (DMD) is an X-linked inherited disorder. Patients present with decreased bone mineral density (BMD) due to glucocorticoid therapy and progressive muscle weakness. Bone remodeling allows bone volume and structure to be maintained and controlled by local and systemic factors. These include the receptor activator of the nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, a determining pathway in the balance between bone formation and resorption. Disruptions in this complex, caused by factors such as glucocorticoids, can affect bone metabolism. The extensive action of the RANK/RANKL/OPG pathway suggests an influence on dystrophic muscle pathophysiology. This review aimed to highlight some aspects of the RANK/RANKL/OPG system, the effect of glucocorticoids on this pathway, and the pathophysiology of the patient with DMD.
Resumen La distrofia muscular de Duchenne (DMD) es un trastorno hereditario ligado al cromosoma X. Los pacientes presentan una disminución de la densidad mineral ósea (DMO) debido a los efectos adversos del tratamiento con glucocorticoides y a la debilidad muscular progresiva. El remodelado óseo permite mantener el volumen y la estructura ósea, proceso controlado por factores locales y sistémicos. Entre ellos destaca el sistema del receptor activador del factor nuclear-kB (RANK), su ligando natural RANKL (RANKL) y la osteoprotegerina (OPG), una vía determinante en el equilibrio entre la resorción y formación ósea. Las alteraciones en este complejo, originadas por factores como los glucocorticoides, pueden afectar el metabolismo óseo. La amplia acción de RANKL y OPG ha sugerido una influencia en la fisiopatología de la DMD. El objetivo de esta revisión fue destacar algunos aspectos del sistema RANK/RANKL/OPG, el efecto de los glucocorticoides en esta vía y la fisiopatología del paciente con DMD.
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Objective:To investigate the mechanism of decomposed Zuoguiwan（ZGW） recipes in treating ovariectomized osteoporosis rats. Method:Forty Sprague-Dawley female rats were equally and randomly divided into Sham-operated group, ovariectomized model group, positive group, and low and high-dose ZGW groups. After 12 weeks of administration by gavage, the bone mineral density (BMD) of rats' distal femur was measured by micro-CT, the morphology of bone tissue were observed by hematoxylin-eosin staining (HE), β-cross-linked c-telopeptide of type Ι collagen (β-CTX) and bone-specific alkaline phosphatase (BALP) in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein expressions of β2AR, OPG and RANKL were evaluated by Western blot analysis and real-time quantitative polymerase chain reaction （PCR）. Result:Compared with Sham-operated group, BMD of rats in ovariectomized model group was decreased (P<0.01), morphology of bone tissue was destroyed, serum BALP was reduced, while β-CTX was boosted (P<0.01)，mRNA and protein expressions of OPG in tibia were reduced, while RANKL were increased, and mRNA and protein expressions of β2AR in the hypothalamus were decreased (P<0.05, P<0.01). Compared with ovariectomized model group, BMDs of rats in low and high-dose ZGW groups were increased (P<0.01), morphology of bone tissue was repaired, serum BALP and mRNA and protein expressions of OPG in tibia were up-regulated (P<0.05, P<0.01), whereas serum β-CTX and mRNA and protein expressions of β2AR in the hypothalamus and RANKL in tibia were down-regulated (P<0.05, P<0.01). Conclusion:Yang-nourishing components in decomposed Zuoguiwan recipes can improve BMD of ovariectomized rats by regulating OPG/RANKL pathway mediated by β2AR. "Seeking Yin in Yang" is a crucial mechanism of Zuoguiwan in treating ovariectomized osteoporosis in rats.
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Objective To investigate the effect of 1,25-(OH)2-vitamin D3 (VD3) or mechanical strain alone and their combined treatment on proliferation and differentiation of pre-osteoblast MC3T3-E1 cells in vitro, as well as gene and protein expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-кB ligand (RANKL) in those cells. Methods MC3T3-E1 cells were treated with 10 nmol/L VD3, intermitted mechanical strain or with a combination of these two factors. Cell proliferation was assessed with flow cytometry, and alkaline phosphatase (ALP) activity was measured using a fluorometric detection kit. The mRNA expression of ALP, runt-related transcriptional factor 2 (Runx2), OPG, and RANKL genes was determined by real-time PCR. The proteins expression of Runx2, OPG, and RANKL was determined by Western blotting. ResultsVD3 inhibited the proliferation of MC3T3-E1 cells, but the mechanical strain had no effect on cell proliferation. Mechanical strain, VD3, and the combined treatment enhanced the ALP activity of MC3T3-E1 cells as well as the protein expression of Runx2. The effect of combined treatment was less pronounced than the effect of VD3 or mechanical strain alone. Mechanical strain promoted the gene and protein expression of osteoprotegerin (OPG) and increased the ratio of OPG/RANKL. However, the combination of VD3 and mechanical strain led to a decrease in ratio of OPG/RANKL. Conclusions Mechanical strain might be effective in inducing osteogenic differentiation and increasing bone formation. A joint stimulation with VD3 and strain can decrease proliferation and osteogenic differentiation and increase RANKL expression, which might affect bone remodeling. This study supplies some new data, which might be important in theoretical and clinical research of osteoporosis (OP) and other related bone diseases.
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Objective:To study the mechanism of the effectiveness loss of methotrexate(MTX)in the treatment of rheumatoid arthri-tis.Methods:The culture system of rat whole bone marrow cells(WBMCs)and tartrateresistant acid phosphatase(TRAP)staining were utilized to evaluate osteoclastogenesis.The mRNA expression of osteoclastogenesis factors in the WBMCs culture system was examined by semi-quantitative RT-PCR.Results:Deoxyadenosine(dAdo)decreased MTX-induced suppression of osteoclastogenesis.The recov-ery effect of dAdo on MTX was partially prevented by caffeine.MTX significantly reduced mRNA expression of receptor activator of nu-clear factor kappa-B ligand(RANKL),dAdo partially recovered RANKL mRNA expression and inhibited osteoprotegerin(OPG)expres-sion.Conclusion:The accumulation of dAdo may induce the effectiveness loss of methotrexate in rheumatoid arthritis treatment.Com-bination of MTX and caffeine can be a potential therapeutic strategy.
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BACKGROUND AND OBJECTIVES: There have been reports of an association between osteoprotegerin (OPG) and cardiovascular disease. Therefore, the aims of this study were to evaluate the association between the plasma OPG level and the severity of atherosclerosis, as well as search for conventional cardiovascular risk factors associated with the plasma OPG level in patients with coronary artery disease (CAD). SUBJECTS AND METHODS: Plasma OPG levels were measured in 583 consecutive patients (mean age: 62+/-10 yrs, M:F=398:185), using an ELISA method, with CAD confirmed from the coronary angiogram. The intima media thickness (IMT) of the common carotid artery was also measured in 252 patients. RESULTS: The plasma OPG level was correlated with the IMT (r=0.184, p=0.003), with the median level found to be elevated in accordance with the severity of CAD (2704 in 1VD vs. 2914 in 2VD vs. 3046 pg/mL in 3VD, p=0.024). Median plasma OPG levels were significantly higher in female (3024 vs. 2828 pg/mL, p=0.003) and DM patients (3098 vs. 2711 pg/mL, p<0.001), and positively correlated with age (r=0.340, p<0.001) and the HbA1C level (r=0.102, p=0.035), but showed an inverse correlation with BMI (r=-0.199, p<0.001). No correlation was found between high sensitive C reactive protein (hs-CRP) and the plasma OPG level, and no relation was found between CRP and the severity of CAD or the IMT. From a multivariate logistic regression analysis, increasing age (odds ratio, 1.053 [95% confidence interval, 1.034-1.073]), DM (odds ratio 1.664 [95% confidence interval, 1.149-2.410]) and a BMI less than 25 kg/mm2 (odds ratio, 1.625 [95% confidence interval, 1.142-2.314]) were associated with the supramedian OPG level (2831 pg/mL). CONCLUSION: The plasma OPG level might be a biochemical marker of atherosclerosis, and is associated with cardiovascular risk factors, especially DM and age.
Subject(s)
Female , Humans , Atherosclerosis , Biomarkers , C-Reactive Protein , Cardiovascular Diseases , Carotid Artery, Common , Coronary Artery Disease , Coronary Vessels , Diabetes Mellitus , Enzyme-Linked Immunosorbent Assay , Logistic Models , Osteoprotegerin , Plasma , Risk FactorsABSTRACT
Objective To investigate the histological and biochemical responses associated with periprosthetic osteolysis,including the changes of tumor necrosis factor-?(TNF-?),osteoprotegerin(OPG) and os- teoprotegeria ligand (OPEL) in the interface membrane in rat models so as to understand the mechanisms of these interactions.Methods Twenty-four male SD rats were used in this study.A titanium alloy plug was inserted into each distal femur through the knee joint.Polyethylene particles were injected into the left knee at 2,4,6,8 and 10 weeks after implantation of the plugs.Saline solution was injected into the right knee as the control.The animals were killed 12 weeks after implantation.The distal femur was taken from each knee to make histological sections. The samples were made decalcified and stained with hematoxylin and eosin.The histopathological changes were observed under a light microscope.The concentrations of TNF-?in the membrane were assayed by a ELISA kit and the mRNA expressions of OPG and OPEL extracted from the tissue around the plug were detected by RT-PCR. Results The interface membrane taken from the experimental side was found to contain extensive fibrous tissues which extended deeply into the surrounding hone.TNF-?concentrations in the membrane of the experimental side were higher than in the control membrane.There was a significant decrease of OPG mRNA and a significant increase of OPGL mRNA in the membrane around the plug at the experimental side compared with the control side.Con- clusions Polyethylene particles can induce inflammatory responses around the titanium alloy plug.The increase of OPGL expression and reduction of OPG expression in membrane at the experimental side may be induced by TNF-?. Such changes might contribute to the differentiation of osteoclasts and result in the periprosthetic osteolysis.
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Objective:To elucidate the effects of calcitonin gene-re la ted peptide(CGRP) on the gene expression of osteoprotegerin(OPG) and receptor ac tivator of nuclear factor-?B ligand(RANKL) in rabbit osteoblasts. Meth ods:Osteoblasts were cultured in media containing 10 -10～10 -7 mol/L of CGRP. After 24-hour incubation,semi-quanitative RT-PCR was perfor med to detect the expression of OPG and RANKL mRNA,and with ?-actin mRNA as th e internal control. Results:CGRP increased the mRNA expressio n of OPG with the maximal effect at the concentration of 10 -8～10 -7 mol/L. CGPR downgulated the mRNA expression of RANKL dose-dependantly.C onclusion:CGRP may regulate the activities of osteoclasts by regulating gene expression of OPG/RANKL.
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Objective:To observe the effect of calcitonin gene-related peptide (CGRP) on the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) in osteoblast cells through an in vitro breast cancer cell and osteoblast cell co-culture system. Methods:The metastatic breast cancer MDA-MB-231 or MDA-MB-435 cells were co-cultured with osteoblast MG63 cells to establish an in vitro microenvironment of bone metastasis of breast cancer. After treated with CGRP(1?108 mol/L),OPG and RANKL mRNA and protein expressions in osteoblast MG63 cells were examined by RT-PCR and Western blotting. Results:Expression of RANKL in osteoblast MG63 cells was up-regulated at both mRNA and protein levels when osteoblast MG63 cells were co-cultured with breast cancer MDA-MB-231 or MDA-MB-435 cells,while those of OPG in osteoblast MG63 cells were both down-regulated (P
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Objective To study the effect of baicalin on the expression of receptor activator of nuclear factor-?B ligand (RANKL) and osteoprotegerin (OPG) in cultured human periodontal ligament cells (HPDL cells) as well as its action mechanism. Methods We first constructed small interferring RNA (siRNA) eukaryotic expression vector targeted transforming growth factor ?Ⅱ receptor (TGF-?RⅡ),and then transfected it into T cells. Then HPDL cells together with T cells transfected with siRNA or not were placed in medium that had been added with lipopolysaccharide (LPS) and baicalin. They were divided into six groups and cultured for 48 hours. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to observe the effect of baicalin on OPG-RANKL expression in HPDL cells. Results The clone sequence correctly identified by RT-PCR was consistent with the designed target sequence. The recombinant vector was constructed successfully and the expression of TGF-?ⅡR of T cells which had been transfected with siRNA1 was inhibited obviously. Ratio of RANKL/OPG in each group differed significantly (P