Increase In Osteoprotegerin Research Articles

Pathogenetic and diagnostic role of osteoprotegerin in the combined course of osteoarthritis and obesity

In recent years, it has been proven that the formation of OA can occur against the background of impaired bone metabolism.
 Bone remodeling is considered as a continuous complex process aimed at eliminating microdamages and updating the bone matrix. A key link in the regulation of this process is the system RANK / RANKL / OPG (osteoprotegerin), which provides a balance of activity of osteoblasts and osteoclasts. It blocks the interaction between RANK and RANKL by intercepting the RANKL ligand, which inhibits osteoclast development and reduces bone resorption.
 Thus, these properties of OPG can be considered as one of the pathogenetic factors in patients with dystrophic joint lesions.
 Objective: to investigate the content and role of osteoprotegerin in young patients with osteoarthritis, which occurs against the background of changes in body weight.
 Materials and methods. The study involved 75 young patients (mean age - 30.92 ± 0.546 years) with overweight or obesity, who in the previous stages of the study was diagnosed with osteoarthritis (main group). The comparison group was represented by 50 patients with osteoarthritis and normal body weight. The age of patients was 30.95 ± 0.545 years; as in the previous group, men predominated - 64% and 36% respectively.
 Benchmarks of osteoprotegerin were obtained in a study of 37 relatively healthy individuals of the same age and sex.
 The level of osteoprotegerin was determined by enzyme-linked immunosorbent assay using the FineTest EH0247 reagent kit, China.
 The outcomes were processed by the methods of variation statistics using the computer program STATISTICA.Results and discussion. When determining the content of OPG in the serum of patients of the main group was found to increase to 124.03 pg / ml, against control - 65.64 pg / ml. In the group of patients with isolated OA, this value was 92.29 pg / ml. Meaning that, in OA, running on the background of altered BMI, the content of OPG is likely to increase, both in relation to the norm and the results of the comparison group (p <0,001).
 The formation and course of osteoarthritis is accompanied by an increase in osteoprotegerin, the content of which depends on the degree of obesity and the radiological stage of the process.
 Conclusions: The course of osteoarthritis is accompanied by an increase in osteoprotegerin, which is considered a negative regulator of bone resorption.
 In osteoarthritis, which occurs against the background of changes in body mass index, a direct correlation with the degree of obesity.
 Changes in osteoprotegerin in patients with osteoarthritis depend on the radiological stage of joint damage and are most pronounced in individuals with stage 2 obesity and stage 2 radiological changes

Hormone and receptor activator of NF-\u03baB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women

BackgroundHormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, we investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women.MethodsWe recruited postmenopausal women at their annual screening mammogram at Washington University School of Medicine, St. Louis. We used the NanoString nCounter platform to quantify gene expression of hormones (prolactin, progesterone receptor (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1 and STAT5), and receptor activator of nuclear factor-kB (RANK) pathway markers (RANK, RANKL, osteoprotegerin, TNFRSF18, and TNFRSF13B) in plasma. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. Linear regression models, adjusted for confounders, were used to evaluate associations between gene expression (linear fold change) and mammographic breast density.ResultsOne unit increase in ESR1, RANK, and TNFRSF18 gene expression was associated with 8% (95% CI 0–15%, p value = 0.05), 10% (95% CI 0–20%, p value = 0.04) and % (95% CI 0–9%, p value = 0.04) higher volumetric percent density, respectively. There were no associations between gene expression of other markers and volumetric percent density. One unit increase in osteoprotegerin and PGR gene expression was associated with 12% (95% CI 4–19%, p value = 0.003) and 7% (95% CI 0–13%, p value = 0.04) lower non-dense volume, respectively.ConclusionThese findings provide new insight on the associations of plasma hormonal and RANK pathway gene expression with mammographic breast density in postmenopausal women and require confirmation in other studies.

Irisin prevents microgravity-induced impairment of osteoblast differentiation in vitro during the space flight CRS-14 mission.

Understanding molecular mechanisms responsible for bone cells unbalance in microgravity would allow the development of better countermeasures for astronauts, and eventually advancing terrestrial osteoporosis treatments. We conduct a unique investigation by using a controlled 3D in vitro cell model to mimic the bone microenvironment in microgravity aboard the SpaceX Dragon cargo ferry to the ISS. Osteoblasts (OBs), osteoclasts (OCs), and endothelial cells (ECs), seeded on Skelite discs, were cultured w/ or w/o rec-Irisin and exposed to 14days of microgravity in the eOSTEO hardware. Gene expression analysis was assessed, and results were compared to ground controls treated within identical payloads. Our results show that the microgravity-induced downregulation of mRNA levels of genes encoding for OB key transcription factors (Atf4 -75%, P<.01; RunX2 -87%, P<.001, Osterix -95%, P<.05 vs ground) and proteins (Collagen I -84%, P<.05; Osteoprotegerin -94%, P<.05) were prevented by irisin. Despite it was not effective in preventing Trap and Cathepsin K mRNA increase, irisin induced a 2.8-fold increase of Osteoprotegerin (P<.05) that might act for reducing osteoclastogenesis in microgravity. Our results provide evidence that irisin supports OB differentiation and activity in microgravity and it might represent a countermeasure to prevent bone loss in astronauts.

Osteoprotegerin as a possible marker of diabetes-associated osteoarthritis

Patients with type 1 diabetes have a higher incidence of osteoarthritis and early manifestation than in the general population. The role of insulin deficiency and hyperglycaemia in the initiation of the destructive process has been proven, but the processes of local and systemic regulation of the balance between anabolic and catabolic processes in the joint and their role in the development of diabetes-associated osteoarthritis remain poorly understood.The aim: to study the role of osteoprotegerin (soluble receptor for tumour necrosis factor - alpha) in the development and progression of diabetes-associated osteoarthritis and its relationship with major metabolic parameters in patients with diabetes mellitus.Materials and methods. 40 patients with type 1 diabetes (17 men and 23 women) were examined, the mean age of the patients was 38.0±2.0 years, the duration of the diabetes was 18.3±1.9 years, the average level of НВА1с was 8.6±0.3 % and 49 patients with type 2 diabetes mellitus (23 men and 26 women), mean age of patients 61.7±1.3 years, duration of diabetes 12.1±1.1 years, mean level HBa1c 7.6±0.1 %. Arthropathy was established in 70.0±7.3 % patients with type 1 diabetes, in 69.4±6.6 % in patients with type 2 diabetes. By sex and type of diabetes, the proportions of patients with and without arthropathy were not statistically different (p&gt; 0.05). The serum content of osteoprotegerin was determined by ELISA using a kit of reagents from Diaclone (France) and enzyme-linked analyser Stat fax 3200 (USA).Results. In patients with arthropathy, a significant increase in osteoprotegerin levels was found. The risk of developing arthropathy in patients with type 1 diabetes with an increased levels of osteoprotegerin is 2.3 times higher than at the normal level (relative risk (RR)=2.33; confidence interval (CI 1.42–3.82; p&lt;0.001), in patients with diabetes 2 type – in 1.55 times (RR=1.55; CI 1.16–1.91). Significant differences in the mean osteoprotegerin level were found for groups absent/present arthropathy. A direct correlation between osteoprotegerin and age was found (p&lt;0.01), diabetes mellitus duration (p &lt;0.05); creatinine level (p&lt;0.05), and an inverse correlation was found with glomerular filtration rate (p&lt;0.05). In the absence of arthropathy, osteoprotegerin and fasting glucose were directly correlated in the type 1 diabetes group (p&lt;0.05). Increased osteoprotegerin levels have been shown to be more common in male patients with longer duration of diabetes. In these patients, no renal lesions were detected, but arthropathy was present as a complication of the underlying disease against the background of an increase in HBA1c.Conclusions. Diabetes-associated osteoarthritis occurs on the background of increased serum osteoprotegerin levels. An increase in the level of osteoprotegerin with an increase in the stage of osteoarthritis was established, so that its level reflects the severity of osteoarthritis. Osteoprotegerin established a direct relationship with the level of creatinine and negatively associated with glomerular filtration rate, i.e. the development and progression of osteoarthritis progression takes place against the background of other vascular complications of diabetes, in particular diabetic nephropathy. An increase in osteoprotegerin is more typical for male patients and depends on the duration of diabetes

Reproductive and Lifestyle Factors and Circulating sRANKL and OPG Concentrations in Women: Results from the EPIC Cohort.

Except for a documented increase in osteoprotegerin (OPG) concentrations with older age, data on determinants of soluble Receptor Activator of Nuclear Factor κB (sRANKL) and OPG concentrations in women are limited. We evaluated reproductive and lifestyle factors as potential sources of variation in circulating sRANKL and OPG concentrations in pre- and postmenopausal women. This study includes 2,016 controls [n = 1,552 (76%) postmenopausal, n = 757 (38%) using postmenopausal hormone therapy (PMH)] from a breast cancer case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Serum sRANKL was measured using an ELISA and serum OPG using an electrochemiluminescent assay. Generalized linear models were used to evaluate associations between these analytes and reproductive and lifestyle factors. Older age at blood collection was associated with lower sRANKL concentrations in postmenopausal women (P trend ≤ 0.03) and higher OPG concentrations in all women (P trend ≤ 0.01). Longer duration of oral contraceptive use among premenopausal women and postmenopausal PMH users was associated with higher OPG (P trend ≤ 0.04). In postmenopausal non-PMH users, sRANKL concentrations were lower with longer duration of oral contraceptive use and current (vs. never) smoking (P ≤ 0.01). sRANKL concentrations were higher among women with higher BMI (P trend ≤ 0.01). The evaluated factors accounted for 12% of the variation in sRANKL concentrations and 21% of the variation in OPG concentrations. Circulating sRANKL and OPG concentrations are minimally impacted by hormone-related factors in pre- and postmenopausal women. This study suggests circulating concentrations of sRANKL and OPG are unlikely to be strongly modified by hormone-related reproductive and lifestyle factors.

Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio

Thrombin and its receptor (TR) are, respectively, expressed in osteoclasts and osteoblasts. However, their physiological roles on bone metabolism have not been fully elucidated. Here we investigated the bone microarchitecture by micro-computed tomography (μCT) and demonstrated increased trabecular and cortical bone mass in femurs of TR KO mice compared to WT littermates. Trabecular thickness and connectivity were significantly enhanced. The physiological role of TR on both inorganic and organic phases of bone is illustrated by a significant increase in BMD and a decrease in urinary deoxypyridinoline (DPD) crosslink concentration in TR KO mice. Moreover, TR KO cortical bone expanded and had a higher polar moment of inertia (J), implying stronger bone. Bone histomorphometry illustrated unaltered osteoblast and osteoclast number and surface in femoral metaphyses, indicating that thrombin/TR regulates osteoblasts and osteoclasts at functional levels. Serum analysis showed a decrease in RANKL and an increase in osteoprotegerin (OPG) levels and reflected a reduced RANKL/OPG ratio in the TR KO group. In vitro experiments using MC3T3 pre-osteoblasts demonstrated a TR-dependent stimulatory effect of thrombin on the RANKL/OPG ratio. This effect was blocked by TR antagonist and p42/p44-ERK inhibitor. In addition, thrombin also intensified p42/p44-ERK expression and phosphorylation. In conclusion, the thrombin/TR system maintains normal bone remodeling by activating RANKL and limiting OPG synthesis by osteoblasts through the p42/44-ERK signaling pathway. Consequently, TR deficiency inhibits osteoclastogenesis, resulting in a high bone mass phenotype.

Vitamin D 3, osteoprotegerin and other hormonal and metabolic parameters in female patients with type 2 diabetes

The article presents the results of evaluation of vitamin D3, osteoprotegerin, carbohydrate and fat metabolic parameters in women with type 2 diabetes and obesity. The study subjects showed an increase of osteoprotegerin, decrease of vitamin D3, insulin resistance and compensatory hyperinsulinemia.

Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength

This review updates our current knowledge on the mechanism of action of strontium ranelate and analyses the way it rebalances bone turnover and how it influences bone biomechanics. Strontium ranelate is able to increase pre-osteoblast replication, osteoblast differentiation, collagen type I synthesis and bone matrix mineralization probably through a calcium-sensing receptor (CaR)-dependent mechanism. Paralleling this anabolic effect there is inhibition of osteoclast differentiation and activity mediated by an increase in osteoprotegerin (OPG) and a decrease in RANK ligand (RANKL). The overall effect is a rebalanced bone turnover in favour of improved bone geometry, cortical thickness, trabecular bone morphology and intrinsic bone tissue quality, which translates into enhanced bone strength.

Bone morphogenetic protein signaling in prostate cancer cell lines.

Prostate cancer is the most commonly diagnosed malignancy in men and is often associated with bone metastases. Prostate cancer bone lesions can be lytic or schlerotic, with the latter predominating. Bone morphogenetic proteins (BMPs) are a family of growth factors, which may play a role in the formation of prostate cancer osteoblastic bone metastases. This study evaluated the effects of BMPs on prostate cancer cell lines. We observed growth inhibitory effects of BMP-2 and -4 on LNCaP, while PC-3 was unaffected. Flow cytometric analysis determined that LNCaP cell growth was arrested in G(1) after bone morphogenetic protein-2 treatment. Treatment of LNCaP and PC-3 with BMP-2 and -4 activated downstream signaling pathways involving SMAD-1, up-regulation of p21(CIP1/WAF1) and changes in retinoblastoma (Rb) phosphorylation. Interestingly, bone morphogenetic protein-2 treatment stimulated a 2.7-fold increase in osteoprotegerin (OPG), a molecule, which inhibits osteoclastogenesis, production in PC-3.