Osteoprotegerin (OPG): A potential biomarker for adverse cardiovascular events in stable coronary artery disease.

Background: Osteoprotegerin (OPG) is a secretory glycoprotein known for its involvement in bone metabolism and immune regulation. Research has extended OPG's significance in cardiovascular diseases (CVDs). Elevated OPG levels have been associated with increased cardiovascular risks, prompting interest in its role as a potential biomarker. Main Body: This study summarizes several studies that investigated the relationship between OPG levels and the incidence of CVD. The studies indicate that higher plasma levels of OPG are associated with an increased incidence of all-cause death, cardiovascular death, and heart failure, even after adjusting for clinical confounders. Moreover, the findings suggest that OPG has the potential to serve as a predictive biomarker for adverse cardiovascular events in the patient population studied. The findings suggest that OPG could aid in risk stratification, allowing clinicians to identify high-risk patients who might benefit from intensified preventive measures or tailored therapeutic interventions. Therefore, early identification of individuals at risk for adverse cardiovascular events could lead to improved patient outcomes and reduced disease burden. Conclusions: OPG's role in bone health and immune regulation has expanded to potential use as a biomarker for adverse cardiovascular events in stable coronary artery disease (CAD) patients. Despite limitations, its association with cardiovascular risks highlights its importance in risk assessment and personalized interventions.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

Oligomeric proanthocyanidins ameliorates osteoclastogenesis through reducing OPG/RANKL ratio in chicken's embryos.

Skeletal disorders can seriously threaten the health and the performance of poultry, such as tibial dyschondroplasia (TD) and osteoporosis (OP). Oligomeric proanthocyanidins (OPC) are naturally occurring polyphenolic flavonoid compounds that can be used as potential substances to improve the bone health and the growth performance of poultry. Eighty 7-day-old green-eggshell yellow feather layer chickens were randomly divided into 4 groups: basal diet and basal diet supplementation with 25, 50, and 100 mg/kg OPC. The results have indicated that the growth performance and bone parameters of chickens were significantly improved supplementation with OPC in vivo, including the bone volume (BV), the bone mineral density (BMD) and the activities of antioxidative enzymes, but ratio of osteoprotegerin (OPG)/receptor activator of NF-κB (RANK) ligand (RANKL) was decreased. Furthermore, primary bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes/macrophages (BMMs) were successfully isolated from femur and tibia of chickens, and co-cultured to differentiate into osteoclasts in vitro. The osteogenic differentiation derived from BMSCs was promoted treatment with high concentrations of OPC (10, 20, and 40 µmol/L) groups in vitro, but emerging the inhibition of osteoclastogenesis by increasing the ratio of OPG/RANKL. In contrary, the osteogenic differentiation was also promoted treatment with low concentrations of OPC (2.5, 5, and 10 µmol/L) groups, but osteoclastogenesis was enhanced by decreasing the ratio of OPG/RANKL in vitro. In addition, OPG inhibits the differentiation and activity of osteoclasts by increasing the autophagy in vitro. Dietary supplementation of OPC can improve the growth performance of bone and alter the balance of osteoblasts and osteoclasts, thereby improving the bone health of chickens.

Changes in Serum Bone Metabolism Markers after Living Donor Liver Transplantation (LDLT) and Their Association with Fracture Occurrences.

Living donor liver transplantation (LDLT) is lifesaving, but can lead to osteoporosis and fractures. In our 3-year study of 25 LDLT recipients, we observed significant reductions in lumbar spine and femoral neck T scores, along with bone resorption marker reductions and liver regeneration marker increases. Serum calcium levels increased, while osteoprotegerin (OPG) decreased and Dickkopf-related protein 1 (DKK-1) increased. Patients who suffered fractures within 3 years of LDLT had higher serum OPG, lower serum nuclear factor kappa B ligand (RANKL), a higher OPG/RANKL ratio and higher serum DKK-1 levels. OPG, RANKL, OPG/RANKL ratio and DKK-1 levels before LDLT predicted hip or spine fractures within three years after LDLT. Further research is necessary to determine the optimal level of osteoclastic activity for preventing fracture onset.

Selected Parameters of Bone Turnover in Neuroendocrine Tumors-A Potential Clinical Use?

BACKGROUND: Currently, there are no effective markers to diagnose and monitor patients with neuroendocrine tumors (NETs). The aim of this study was to assess bone metabolism based on selected markers of bone turnover: OST, OPG, and IGFBP-3, in both the group of patients with NETs and the control group. Associations with selected sociodemographic, biochemical, and clinicopathological characteristics were examined. We also evaluated any potential associations between these markers and selected biochemical markers of NETs commonly used in clinical practice. METHODS: The study group included 60 patients with GEP-NETs and BP-NETs, while the control group comprised 62 healthy individuals. The serum concentrations of OST, OPG and IGFBP-3 were assessed using ELISA. RESULTS: OST and OPG levels were significantly higher in the study group compared to the control group. In the study group, we observed a significant correlation between OPG and the clinical stage and chromogranin A. Additionally, an association was found between OPG and histological grade, Ki-67, and metastasis in GEP-NET cases. CONCLUSIONS: Markers of bone turnover cannot be used in the routine diagnostics of neuroendocrine tumors. Nonetheless, these markers may help evaluate the skeletal system in patients with NETs. Further research is needed to determine the utility of osteocalcin (OST) and osteoprotegerin (OPG) as potential biomarkers for neuroendocrine tumors.

Plasma osteoprotegerin predicts adverse cardiovascular events in stable coronary artery disease: the PEACE trial.

Background: Osteoprotegerin (OPG) is a secretory glycoprotein and participates in the progression of atherosclerotic lesions. We aim to explore the relationship between OPG and the prognosis of coronary artery disease (CAD). Methods: Plasma OPG concentrations were measured in 3,766 patients with stable CAD enrolled in the PEACE trial. The PEACE trial (NCT00000558) group followed up the patients and examined their future clinical outcomes. Results: In summary, 208 (5.5%) primary outcomes occurred, 295 patients (7.8%) died from all-cause death, 128 (3.4%) died from cardiovascular causes, and 94 (2.5%) experienced heart failure during a median follow-up of 1,892 days. In addition, we found that higher plasma levels of OPG were associated with a higher incidence of all-cause death, cardiovascular death, and heart failure, even after adjusting clinical cofounders. Conclusion: It was demonstrated that elevated plasma OPG levels were associated with an increased incidence of all-cause death, cardiovascular death, and heart failure in patients with stable CAD. Systematic Review Registration: https://clinicaltrials.gov/ct2/show/NCT00000558?term=NCT00000558&draw=2&rank=1, identifier: NCT00000558.

Bone Remodeling Markers in Children with Acute Lymphoblastic Leukemia after Intensive Chemotherapy: The Screenshot of a Biochemical Signature.

PURPOSE: to investigate the effects of intensive chemotherapy and glucocorticoid (GC) treatment on bone remodeling markers in children with acute lymphoblastic leukemia (ALL). METHODS: A cross-sectional study was carried out in 39 ALL children (aged 7.64 ± 4.47) and 49 controls (aged 8.7 ± 4.7 years). Osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), bone alkaline phosphatase (bALP), tartrate-resistant acid phosphatase 5b (TRACP5b), procollagen type I N-terminal propeptide (P1NP), Dickkopf-1 (DKK-1), and sclerostin were assessed. Statistical analysis was conducted using the principal component analysis (PCA) to study patterns of associations in bone markers. RESULTS: ALL patients showed significantly higher OPG, RANKL, OC, CTX, and TRACP5b than the controls (p ≤ 0.02). Considering ALL group, we found a strong positive correlation among OC, TRACP5b, P1NP, CTX, and PTH (r = 0.43-0.69; p < 0.001); between CTX and P1NP (r = 0.5; p = 0.001); and between P1NP and TRAcP (r = 0.63; p < 0.001). The PCA revealed OC, CTX, and P1NP as the main markers explaining the variability of the ALL cohort. CONCLUSIONS: Children with ALL showed a signature of bone resorption. The assessment of bone biomarkers could help identify ALL individuals who are most at risk of developing bone damage and who need preventive interventions.

Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview.

Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κß ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.

Traditional Chinese Medicine in Prevention and Treatment of Osteonecrosis of Femoral Head Based on OPG/RANK/RANKL Signaling Pathway： A Review / 中国实验方剂学杂志

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.

Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice.

Objective: Knee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms. Methods: In vivo study, eight-week-old male mice including wild-type (WT) (n â€‹= â€‹54) and OPG-/- (n â€‹= â€‹54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n â€‹= â€‹18), the DMM group (WT-DMM; n â€‹= â€‹18), and the PTH (1-34)-treated group (WT-DMM â€‹+ â€‹PTH (1-34); n â€‹= â€‹18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro. Results: Compared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6). Conclusion: Both wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA. The translational potential of this article: Systemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.

S-Equol enhances osteoblastic bone formation and prevents bone loss through OPG/RANKL via the PI3K/Akt pathway in streptozotocin-induced diabetic rats.

Background: This study aimed to explore whether S-Equol delays diabetes-induced osteoporosis and the molecular mechanisms underlying its therapeutic effects. Materials and methods: Thirty-five male Sprague-Dawley rats were randomized into five groups. The diabetic osteoporosis (DOP) group and three S-Equol treatment groups were intraperitoneally injected with streptozotocin (STZ) to develop a DOP model. After the 12-week intervention, bone transformation indicators were detected using an enzyme-linked immunosorbent assay kit; bone mineral density (BMD) and bone microstructure were obtained using dual-energy X-ray absorptiometry and microCT; morphological changes in the bone tissue were investigated using HE staining; bone morphogenetic proteins were detected using immunohistochemical staining. ROS17/2.8 cells were cultured in vitro, and Cell Counting Kit-8 was used to test the protective effects of S-Equol in osteoblastic cells in a high-fat and high-glucose environment. Furthermore, the expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), estrogen receptor ß(ERß), phosphorylated Akt (pAKT)/protein kinase B (AKT), and osteocalcin (OC) in bone tissue and ROS17/2.8 cells was assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. To determine whether ERß and phosphatidylinositol 3' -kinase (PI3K)/AKT signaling pathways are involved in the process, LY294002 (PI3K signaling pathway inhibitor) and small interfering RNA targeting ERß mRNA (si-ERß) were used to verify the function of the ERß-mediated PI3K/AKT pathway in this process. Results: After the 12-week intervention, S-Equol enhanced BMD, improved bone microarchitecture in DOP rats (P < 0.05), and improved markers of bone metabolism (P < 0.05). In vitro, 10-6 mmol/L S-Equol was selected to significantly protect osteoblasts from high- and high-glucose environments (P < 0.05). Gene expression of OPG, ERß, pAKT/AKT, and OC was upregulated compared to the DOP group, and RANKL was downregulated compared to the DOP group (P < 0.05) both in bone tissue and osteoblastic cells. The promotion of OPG and pAKT/AKT is mediated by LY294002 and siERß. Conclusion: S-Equol binds to ERß to regulate OPG/RANKL via the PI3K/AKT pathway and improve DOP. Our results demonstrate the potential role of S-Equol in the treatment of DOP by targeting ERß. Thus, S-Equol may have the potential to be an adjuvant drug for treating DOP.

Escaping cell death via TRAIL decoy receptors: a systematic review of their roles and expressions in colorectal cancer.

The development of targeted therapy such as tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-based therapy has gained increasing attention as a promising new approach in cancer therapy. TRAIL specifically targets cancer cells while sparing the normal cells, thus, limiting the known side effects of the majority anti-cancer therapies. As more extensive research and clinical trials are conducted, resistance to TRAIL molecule has become one of the significant issues associated with the failure of TRAIL in treating colorectal cancer (CRC). To date, the exact mechanism by which TRAIL resistance may have occurred remains unknown. Interestingly, recent studies have revealed the critical role of the TRAIL decoy receptor family; consisting of decoy receptor 1 (DcR1; also known as TRAIL-R3), decoy receptor 2 (DcR2; also known as TRAIL-R4), and osteoprotegerin (OPG) in driving TRAIL resistance. This review highlights the expression of the decoy receptors in CRC and its possible association with the reduction in sensitivity towards TRAIL treatment based on the currently available in vitro, in vivo, and human studies. Additionally, discrepancies between the outcomes from different research groups are discussed, and essential areas are highlighted for future investigation of the roles of decoy receptors in modulating TRAIL-induced apoptosis. Overcoming TRAIL resistance through modulating the expression(s) and elucidating the role(s) of TRAIL decoy receptors hold great promise for TRAIL-based therapies to be extensively explored in treating human cancers including CRC.

Duchenne muscular dystrophy: RANK/RANKL/OPG (receptor activator of nuclear factor-kB/RANK ligand/osteoprotegerin) system and glucocorticoids.

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.

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.

Duchenne muscular dystrophy: RANK/RANKL/OPG (receptor activator of nuclear factor-kB/RANK ligand/osteoprotegerin) system and glucocorticoids / Distrofia muscular de Duchenne: el sistema RANK/RANKL/OPG (receptor activador del factor nuclear-kB/ligando de RANK/osteoprotegerina) y glucocorticoides

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.

Impact of the Rapid Normalization of Chronic Hyperglycemia on the Receptor Activator of Nuclear Factor-Kappa B Ligand and the Osteoprotegerin System in Patients Living with Type 2 Diabetes: RANKL-GLYC Study.

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Omega 3 fatty acids effect on the vascular calcification biomarkers fetuin A and osteoprotegerin in hemodialysis patients.

Chronic renal failure patients on dialysis are at a high risk of death due to vascular calcification. This study aimed at investigating the effect of omega-3 fatty acids on the vascular calcification biomarkers fetuin-A and osteoprotegerin (OPG) in patients with chronic renal failure who are undergoing hemodialysis. This prospective, open-label, controlled, parallel study included 60 hemodialysis patients who were randomized to receive either omega-3 fatty acids capsule along with their standard care of treatment (omega-3 group) or their standard care of treatment only (control group). Serum levels of fetuin-A, OPG, calcium, phosphorus, hemoglobin, parathyroid hormone, blood urea nitrogen (BUN), albumin, serum creatinine (SCr), and serum triglycerides (TG) were measured at baseline and after six months of intervention and follow-up of both groups. Significantly increased levels of fetuin-A and OPG (p < 0.001) were observed in the omega-3 group six months after the intervention compared with the control group. Levels of TG, albumin, SCr, BUN, phosphorous, calcium, hemoglobin, and parathyroid hormone were not significantly different in the omega-3 group compared with the control group after six months of intervention. Our study concluded that omega-3 may have a clinically beneficial effect in decreasing cardiovascular events by increasing the levels of the protective vascular calcification inhibitors fetuin-A and osteoprotegerin in chronic renal failure patients who are undergoing hemodialysis.

Beclin 1 positively regulates osteoprotegerin-induced inhibition of osteoclastogenesis by increasing autophagy in vitro.

Osteoclastogenesis is induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), and can be suppressed by osteoprotegerin (OPG). Beclin1 has a dual role in osteoclastogenesis. However, the role of Beclin1-mediated autophagy during OPG-induced inhibition of osteoclastogenesis remains unclear. Here, we found that Beclin1 and matrix metalloproteinase 9 (MMP-9) expression were increased during osteoclastogenesis. OPG (20, 40, and 80 ng/mL) decreased Src and MMP-9 expression, but augmented Beclin1 expression and fluorescence intensity. Similarly, treatment with the autophagy activator rapamycin increased Beclin1 expression during OPG-induced inhibition of osteoclastogenesis. Further, Beclin1 knockdown restored osteoclast numbers by reducing autophagy during OPG-induced inhibition of osteoclastogenesis. These results indicate that Beclin1 has a positive role during OPG-induced inhibition of osteoclastogenesis by regulating autophagy, which might provide a potential basis for osteoclastogenesis.

The Pathophysiology of Osteoporosis after Spinal Cord Injury.

Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.

Regulation of TNF-Induced Osteoclast Differentiation.

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFß1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Systemic osteoprotegerin does not improve peri-implant bone volume or osseointegration in rabbits.

Anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agents function by blocking the differentiation of osteoclasts, thereby proving useful in the clinical management of postmenopausal osteoporosis. The effects of such agents on osseointegration is less well understood. The purpose of the current study was to investigate whether osteoprotegerin (OPG), an osteoclast inhibitor, enhances the known anabolic effects of mechanical loading (VEH) and intermittent PTH (iPTH) using a well-established rabbit model of osseointegration. In the first set of experiments, OPG was administered either alone or combined with iPTH to study its effects on measured bone mass. The second set of experiments was conducted using a higher dosage of OPG (10 mg/kg) to explore its early impact at the cellular and molecular levels. All subjects had mechanical load applied to the implant on one extremity, and no load applied on the contralateral side. In the first set of experiments, OPG alone decreased peri-implant bone mass compared to the mechanical loading group, whereas OPG + iPTH increased peri-implant bone mass compared to the OPG group. In the second set of experiments, high-dose OPG significantly decreased osteoclast number (-74.3%) at 1 week. However, this effect was not sustained as osteoclast number returned to baseline by 2 weeks. These results suggest that systemic administration of OPG does not enhance osseointegration, but rather has a detrimental effect.