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Journal of Traditional Chinese Medicine... Dec 2018To determine the effect of an esculetin formulation (at 97.4% purity) on osteoporosis, and to investigate the potential underlying molecular mechanism(s).
OBJECTIVE
To determine the effect of an esculetin formulation (at 97.4% purity) on osteoporosis, and to investigate the potential underlying molecular mechanism(s).
METHODS
Sixty specific pathogen free-grade female Wistar rats were randomly assigned to three groups: blank control (n = 12), sham (n = 12), and model (n = 36). The model group were bilaterally ovariectomized. The sham group had the tissue surrounding the ovaries removed, while the ovaries were retained. After 3 months, the model group was randomly divided into three subgroups: OVX (n = 12), positive control (n = 12), and esculetin (n = 12). The positive control group and the esculetin group were intragastrically administered diethylstilbestrol (0.046 mg?kg-1?d-1) or esculetin (384 mg?kg-1?d-1), respectively, once per day for 6 consecutive days; medication administration was then stopped for 1 d, before being administered for another 6 consecutive days. All rats were treated for 3 months. Samples were collected at the end of the treatment period. An Osteocore3 Digital 2D bone densitometer was used to test the bone mineral density, and histomorphometric analysis was performed to measure bone mass, bone formation, and bone resorption. Enzyme-linked immunosorbent assay analysis was used to measure the serum concentrations of interleukin-6 (IL-6), osteoprotegerin (OPG), and receptor activator of nuclear factor-kappa B ligand (RANKL). Immunohistochemistry and in situ hybridization were performed to detect the protein and mRNA expressions of OPG and RANKL in osteoblasts and bone marrow stromal cells.
RESULTS
Compared with the OVX group, the esculetin group had significantly greater femoral bone mineral density and tibial trabecular bone volume, and significantly smaller trabecular resorption surface. The percentage of trabecular formation surface, average osteoid width, trabecular bone mineralization rate, and cortical bone mineralization rate did not significantly differ between groups. Compared with the sham group, the esculetin group had significantly decreased serum levels of IL-6 and RANKL, and significant downregulation of RANKL protein and mRNA expression levels in osteoblasts and bone marrow stromal cells; however, there was no significant difference between groups in OPG.
CONCLUSION
Esculetin can increase bone mass by upregulating RANKL expression in osteoblasts and bone marrow stromal cells, and decreasing serum IL-6 concentration. This indicates that the therapeutic effect of esculetin on osteoporosis occurs via decreased bone resorption.
Topics: Animals; Bone Density; Calcification, Physiologic; Drugs, Chinese Herbal; Female; Fraxinus; Humans; Interleukin-6; Osteoblasts; Osteoporosis; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Rats, Wistar; Umbelliferones
PubMed: 32186137
DOI: No ID Found -
Clinical Orthopaedics and Related... Dec 2014Identification of biomarkers associated with wear and tribocorrosion in joint arthroplasty would be helpful to enhance early detection of aseptic loosening and/or... (Review)
Review
BACKGROUND
Identification of biomarkers associated with wear and tribocorrosion in joint arthroplasty would be helpful to enhance early detection of aseptic loosening and/or osteolysis and to improve understanding of disease progression. There have been several new reports since the last systematic review (which covered research through mid-2008) justifying a new assessment.
QUESTIONS/PURPOSES
We sought to determine which biomarkers have the most promise for early diagnosis and monitoring of aseptic loosening and/or osteolysis related to wear or corrosion in total joint arthroplasty.
METHODS
We performed a systematic review using MEDLINE and EMBASE databases, covering the period through December 2013, and identified 1050 articles. We restricted the definition of biomarker to biomolecules and imaging parameters useful for diagnosis and monitoring of disease progression, only including articles in English. We chose 65 articles for full review, including 44 from the original search and 21 from subsequent hand searches. We used the 22 articles in which patients with total joint arthroplasty who had aseptic loosening and/or periimplant osteolysis unrelated to sepsis had been compared with patients with total joint arthroplasty with stable implants. There were 90 comparisons of these two patient populations involving 35 different biomarkers.
RESULTS
Diagnostic accuracy was assessed in nine of the 90 comparisons with the highest accuracy found for tartrate-resistant acid phosphatase 5b (0.96), although a separate comparison for this biomarker found a lower accuracy (0.76). Accuracy of > 0.80 was also found for crosslinked n-telopeptide of type I collagen, osteoprotegerin, and deoxypyridinoline. The most studied markers, tumor necrosis factor-α and interleukin-1β, were found to differ in the affected and control groups in < 30% of the comparisons. Thirty of the 35 biomarkers were studied in four or fewer separate comparisons with nearly half of the biomarkers (17) studied in only one comparison. Many of the comparisons were not able to eliminate a number of confounding variables, and there was only one prospective study.
CONCLUSIONS
Currently, there are no validated biomarkers for early diagnosis and monitoring of the biological sequelae of wear or tribocorrosion, although there are some promising leads, including markers of bone turnover.
Topics: Arthroplasty, Replacement; Biomarkers; Biomechanical Phenomena; Corrosion; Diagnostic Imaging; Humans; Joint Prosthesis; Joints; Osteolysis; Predictive Value of Tests; Prosthesis Design; Prosthesis Failure; Risk Factors; Stress, Mechanical; Treatment Outcome
PubMed: 24668073
DOI: 10.1007/s11999-014-3580-3 -
Expert Opinion on Therapeutic Targets Sep 2010Osteoporosis has become a worldwide health and social issue due to an aging population. Four major antiresorptive drugs (agents capable of inhibiting osteoclast... (Review)
Review
IMPORTANCE OF THE FIELD
Osteoporosis has become a worldwide health and social issue due to an aging population. Four major antiresorptive drugs (agents capable of inhibiting osteoclast formation and/or function) are currently available on the market: estrogen, selective estrogen receptor modulators (SERMs), bisphosphonates and calcitonin. These drugs either lack satisfactory efficacy or have potential to cause serious side effects. Thus, development of more efficacious and safer drugs is warranted.
AREAS COVERED IN THIS REVIEW
The discovery of the receptor activator of NF-kappaB ligand (RANKL) and its two receptors, RANK and osteoprotegerin (OPG), has not only established a crucial role for the RANKL/RANK/OPG axis in osteoclast biology but also created a great opportunity to develop new drugs targeting this system for osteoporosis therapy. This review focuses on discussion of therapeutic targeting of RANK signaling.
WHAT THE READER WILL GAIN
An update on the functions of RANKL and an overview of the known RANK signaling pathways in osteoclasts. A discussion of rationales for exploring RANK signaling pathways as potent and specific therapeutic targets to promote future development of better drugs for osteoporosis.
TAKE HOME MESSAGE
Several RANK signaling components have the potential to serve as potent and specific therapeutic targets for osteoporosis.
Topics: Animals; Drug Delivery Systems; Drug Design; Humans; Osteoporosis; Osteoprotegerin; RANK Ligand; Signal Transduction
PubMed: 20678025
DOI: 10.1517/14728222.2010.511179 -
The Journal of Clinical Endocrinology... Nov 2005The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the... (Review)
Review
CONTEXT
The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor.
EVIDENCE
This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease.
EVIDENCE SYNTHESIS
Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements.
CONCLUSIONS
The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.
Topics: Bone Diseases, Metabolic; Carrier Proteins; Female; Fracture Healing; Glycoproteins; Humans; Male; Membrane Glycoproteins; Neoplasms; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Factors; Vascular Diseases
PubMed: 16105967
DOI: 10.1210/jc.2005-0794 -
Cells Apr 2022Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of...
Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of well-being in which relapses have a softer evolution, particularly in the third trimester. Herein, we hypothesized that the placenta, via its "secretome", could contribute to the recognized beneficial effects of pregnancy on MS activity. We focused on a well-known receptor/ligand/decoy receptor system, such as the one composed by the receptor activator of nuclear factor-kB (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG), which have never been investigated in an integrated way in MS, pregnancy, and placenta. We reported that pregnancy at the term of gestation influences the balance between circulating RANKL and its endogenous inhibitor OPG in MS women. We demonstrated that the placenta at term is an invaluable source of homodimeric OPG. By functional studies on astrocytes, we showed that placental OPG suppresses the mRNA expression of the CCL20, a chemokine responsible for Th17 cell recruitment. We propose placental OPG as a crucial molecule for the recognized beneficial effect of late pregnancy on MS and its potential utility for the development of new and more effective therapeutic approaches.
Topics: Female; Humans; Ligands; Multiple Sclerosis; Osteoprotegerin; Placenta; Pregnancy; Protein Binding; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B
PubMed: 35456036
DOI: 10.3390/cells11081357 -
PloS One 2016Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of...
BACKGROUND
Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington's disease gene carriers (premanifest and moderate stage II/III) and controls.
METHODS
Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test.
RESULTS
We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington's disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious.
CONCLUSIONS
Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington's disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington's disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results, despite many being tested, suggests that the majority of these markers do not differ markedly by disease status.
Topics: Adult; Aged; Biomarkers; Blood Glucose; Carbohydrate Metabolism; Case-Control Studies; Female; Ghrelin; Human Growth Hormone; Humans; Huntington Disease; Hydrocortisone; Insulin; Leptin; Lipid Metabolism; Male; Middle Aged
PubMed: 26744893
DOI: 10.1371/journal.pone.0146480 -
Computational Intelligence and... 2022The target of the present paper was to reveal the influence of LncRNA BC083743 on osteogenesis in human bone marrow mesenchymal stem cells (hBMSCs).
OBJECTIVE
The target of the present paper was to reveal the influence of LncRNA BC083743 on osteogenesis in human bone marrow mesenchymal stem cells (hBMSCs).
METHODS
Serum specimens from osteoporotic patients and normal subjects were collected to isolate hBMSCs from femoral head tissue. The levels of BC083743 and miR-103-3p in serum and hBMSCs were measured by QRT-PCR. Alkaline phosphatase (ALP) activity test and alizarin red dyeing were used to identify ALP activity and mineralization forming ability of hBMSCs after transfection with si-BC083743 (siRNA-targeting BC083743). In addition, QRT-PCR and immunoblotting were conducted to identify the expressing levels of Runt-related transcription factor 2(Runx2), osteoprotegerin (OPG), and bone morphogenetic protein 2 (BMP2) in hBMSCs. Dual-luciferase reporter gene and RNA pull-down assays were employed to substantiate the binding of BC083743 to miR-103-3p and miR-103-3p to SATB2.
RESULTS
BC083743 expression was significantly downregulated in sera from patients with osteoporosis, and osteogenic differentiation-related genes and BC083743 expression were obviously upregulated as the time to osteogenic differentiation increased. BC083743 knockdown hindered the osteogenic differentiation of hBMSCs. BC083743 was aimed at miR-103-3p and miR-103-3p inhibitors partially reversed the inhibitory effect of BC083743 downregulation on hBMSCs osteogenesis. BC083743 silencing downregulated SATB2 through uptake of miR-103-3p, thereby inhibiting hBMSCs osteogenesis to exacerbate osteoporosis.
CONCLUSION
BC083743/miR-103-3p/SATB2 axis inhibited osteogenic differentiation and exacerbated osteoporosis, which may offer brand-new molecular aims for the treatment of clinical osteoporosis.
Topics: Cells, Cultured; Humans; Matrix Attachment Region Binding Proteins; MicroRNAs; Osteogenesis; Osteoporosis; RNA, Long Noncoding; Transcription Factors
PubMed: 35769281
DOI: 10.1155/2022/7066759 -
Clinica Chimica Acta; International... Jan 2013Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests...
BACKGROUND
Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods.
METHODS
Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers.
RESULTS
Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis.
CONCLUSION
Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value.
Topics: Adult; Apolipoprotein A-I; Aspartate Aminotransferases; Biomarkers; Collagen Type IV; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Research Design; Sensitivity and Specificity; Severity of Illness Index; alpha-Macroglobulins
PubMed: 23022619
DOI: 10.1016/j.cca.2012.09.020 -
Journal of Personalized Medicine Jun 2021This work is aimed at studying the relationship of matrix metalloproteinases with calcification of the coronary arteries. The study included 78 people with coronary...
This work is aimed at studying the relationship of matrix metalloproteinases with calcification of the coronary arteries. The study included 78 people with coronary heart disease (CHD) and 36 without CHD. Blood and samples of coronary arteries obtained as a result of endarterectomy were examined. Serum levels of metalloproteinases (MMP) MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13 were determined by multiplex analysis. In blood vessel samples, MMP-1, MMP-3, MMP-7, and MMP-9 were determined by enzyme immunoassay; MMP-9 expression was evaluated by immunohistochemistry. Patients with CHD had higher serum levels of MMP-1, MMP-7, and MMP-12. Blood levels of MMP-1 and MMP-3 were associated with calcium levels, MMP-9 with osteoprotegerin and osteonectin, MMP-7 and MMP-10 with osteoprotegerin, MMP-12 with osteocalcin, and MMP-13 with osteopontin. Calcified plaques had higher levels of MMP-1 and MMP-9 compared to plaques without calcification. The relative risk of coronary arteries calcification was associated with MMP-9, which is confirmed by the results of immunohistochemistry. The results obtained indicate the participation of some MMPs, and especially MMP-9, in the calcification processes. The study can serve as a basis for the further study of the possibility of using MMP-1, MMP-7 and MMP-12 as potential biomarkers of CHD.
PubMed: 34205079
DOI: 10.3390/jpm11060506 -
Journal of Musculoskeletal & Neuronal... Sep 2004The molecular and physiological mechanisms of control of osteoclast formation and activity have been explained with the discovery of three members of the Tumour Necrosis... (Review)
Review
The molecular and physiological mechanisms of control of osteoclast formation and activity have been explained with the discovery of three members of the Tumour Necrosis Factor superfamily. Receptor activator of NF-kappaB ligand (RANKL) is the type II membrane protein in cells of the osteoblastic lineage which interacts with its receptor, RANK, on hemopoietic precursors to promote osteoclast formation and maintain their viability and activity. The process is further regulated by the decoy receptor, osteoprotegerin (OPG), also produced by stromal/osteoblastic cells, and which binds to RANKL to prevent RANKL stimulation of osteoclast formation. These discoveries fulfilled predictions that came from more than 20 years of research in bone cell biology in predominantly rodent systems. The hypothesis that the osteoblast lineage directed osteoclast function introduced the concept of intercellular communication in bone. It needed new methods to be developed to test it, and there were many who contributed to this. With a number of identifiable milestones from the early 1980s on, a highly convincing case was made for the existence of what turned out to be RANKL and RANK. As it happened, OPG came first, and the background biological information was so instructive that it was obvious that OPG would lead to the final answer. By that stage the necessary methods were all in place, and in a short time all the key molecular regulators were identified. Ultimate proof of their physiological importance came from genetic experiments in mice.
Topics: Animals; Bone and Bones; Humans; Osteoclasts; Paracrine Communication
PubMed: 15615492
DOI: No ID Found