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RANK/RANKL/OPG/LGR4 signaling in bone. a Osteoblasts synthesize and secrete RANKL which binds RANK allowing their activation, maturation and prolonging the survival of osteoclasts. b Osteoblasts also secrete OPG, a soluble RANKL decoy receptor, which prevents RANKL binding to RANK, inhibiting osteoclastogenesis. c RANKL can also bind the LGR4 receptor on the surface of the osteoblasts, triggering signals of mineralization and bone formation
Source publication
In the course of chronic kidney disease (CKD), alterations in the bone-vascular axis augment the risk of bone loss, fractures, vascular and soft tissue calcification, left ventricular hypertrophy, renal and myocardial fibrosis, which markedly increase morbidity and mortality rates. A major challenge to improve skeletal and cardiovascular outcomes i...
Citations
... Regarding kidney injury, the activation of Wnt signaling appears to have reparative effects in AKI, but its sustained activation becomes deleterious in CKD [32,33]. DKK1, an inhibitor of the LRP5/6 co-receptor, has been used in several studies to interrupt classical Wnt signaling [34]. Notably, DKK1 can inhibit myofibroblast activation and, ultimately, fibrosis in mice with obstructive injury [35]. ...
Background: Renal fibrosis is the primary pathway in the progression of chronic kidney disease (CKD) towards end-stage renal failure. The currently used drugs currently are ineffective, and their mechanisms of action remain unclear. This study aims to investigate the nephroprotective effect of Improved-Nephropathy 1 Formula (N1F) in a rat model of unilateral ureteral obstruction (UUO) and explore the potential mechanisms of N1F-containing serum in treating TGF-ß1-induced human renal tubular epithelial cells (HK-2). Methods: SD rats received 2-week continuous N1F gavage starting on day 2 after UUO. HK-2 cells were pretreated with a P38MAPK inhibitor for 1 h in vitro, followed by induction of the cells with TGF-ß1 and treatment with N1F 48 h later. The chemical composition of N1F was analyzed using high-performance liquid chromatography-Q-Orbitrap high-resolution liquid mass spectrometry. Renal function was assessed by measuring serum creatinine (Scr), blood urea nitrogen (BUN) and urine protein (Upro) levels. Hematoxylin and eosin (HE) and Masson’s trichrome (Masson) staining were used to evaluate the extent of renal tissue damage and fibrosis. Western blotting, immunohistochemistry, and immunofluorescence were used to detect the protein levels of relevant indices. The RNA levels of the relevant indices were detected using real-time fluorescence quantitative PCR (RT-qPCR). Results: We identified 361 chemical components in the water extract of N1F. These chemical components of N1F significantly reduced the area associated with interstitial fibrosis in the kidneys of UUO rats and the levels of serum creatinine, urea nitrogen, and urinary protein. Additionally, N1F decreased the protein levels of FGF23, Wnt1, ß-catenin and p-P38MAPK/P38MAPK, along with the expression of renalfibrosis-associated proteins, α-SMA, FN, Collagen III, and Vimentin in the renal tissues of the UUO rats, while enhancing klotho and DKK1 protein levels. In vitro experiments revealed that inhibition of P38MAPK signaling significantly suppressed the expression of proteins related to the Wnt signaling pathway, with a concomitant decrease in the expression of FGF23 and an increase in the expression of Klotho. Notably, the P38MAPK inhibitor (SB203580) had similar effects to N1F in altering the above-mentioned indices in vitro. Conclusions: N1F may exhibit potential therapeutic efficacy against renal fibrosis by inhibiting the FGF23/P38MAPK/Wnt signaling pathway, consequently inhibiting extracellular matrix deposition due to renal injury.
Graphical Abstract
... Romosozumab, an anti-sclerostin treatment, presents a promising avenue for preventing and treating fractures in osteoporosis among postmenopausal women; however, potential negative cardiovascular effects need careful consideration [41,68,70,71]. ...
Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
... Regarding kidney injury, the activation of Wnt signaling appears to have reparative effects in AKI, but its sustained activation becomes deleterious in CKD [28] [29]. DKK1, an inhibitor of the LRP5/6 co-receptor, has been used in several studies to interrupt classical Wnt signaling [30]. Notably, DKK1 can inhibit myofibroblast activation and, ultimately, fibrosis in mice with obstructive injury [31]. ...
Background: Renal fibrosis is the primary pathway in the progression of chronic kidney disease (CKD) towards end-stage renal failure. The currently used drugs currently are ineffective, and their mechanisms of action remain unclear. This study aims to investigate the nephroprotective effect of Improved-Nephropathy 1 Formula (N1F) in a rat model of unilateral ureteral obstruction (UUO) and explore the potential mechanisms of N1F-containing serum in treating TGF-β1- induced human renal tubular epithelial cells (HK-2).
Methods: The chemical composition of N1F was analyzed using high-performance liquid chromatography-Q-Orbitrap high-resolution liquid mass spectrometry. Renal function was assessed by measuring serum creatinine (Scr), blood urea nitrogen (BUN) and urine protein (Upro) levels. Hematoxylin and eosin (HE) and Masson’s trichrome (Masson) staining were used to evaluate the extent of renal tissue damage and fibrosis. Western blotting, immunohistochemistry, and immunofluorescence were used to detect the protein levels of relevant indices. The RNA levels of the relevant indices were detected using real-time fluorescence quantitative PCR (RT-qPCR).
Results: We identified 361 chemical components in the water extract of N1F. These chemical components of N1F significantly reduced the area associated with interstitial fibrosis in the kidneys of UUO rats and the levels of serum creatinine, urea nitrogen, and urinary protein. Additionally, N1F decreased the protein levels of FGF23, Wnt1, β-catenin and p-P38MAPK/P38MAPK, along with the expression of renalfibrosis-associated proteins, α-SMA, FN, Collagen III, and Vimentin in the renal tissues of the UUO rats, while enhancing klotho and DKK1 protein levels. In vitro experiments revealed that inhibition of P38MAPK signaling significantly suppressed the expression of proteins related to the Wnt signaling pathway, with a concomitant decrease in the expression of FGF23 and an increase in the expression of Klotho.Notably, the P38MAPK inhibitor (SB203580) had similar effects to N1F in altering the above-mentioned indices in vitro.
Conclusions: N1F may exhibit potential therapeutic efficacy against renal fibrosis by inhibiting the FGF23/P38MAPK/Wnt signaling pathway, consequently inhibiting extracellular matrix deposition due to renal injury.
... The net increase in the number and activity of osteoclasts results in increased bone resorption through the secretion of acid and lithic enzymes (tartrate-resistant acid phosphatase and cathepsin K), which degrade the extracellular compartment. During resorption process, osteoclasts also release factors that stimulate bone formation (BMP6, WNT10B) or are involved in immune response (clastokines) [11]. ...
... OPG expression is regulated by a variety of factors. Thus, it is increased by cytokines (TNF alpha, IL 1, IL18 TGF beta), morphogenetic proteins (BMPs) and steroid hormones (17beta estradiol) and decreased by glucocorticoids, PTH and E2 prostaglandin [11]. ...
Bone is more than a reservoir of calcium and phosphorus. Its lacuno-canalicular arrangement provides an important pathway for exchange with circulation and currently, the skeleton is considered a large endocrine organ with actions that go beyond the control of calcium-phosphorus balance mediated by fibroblastic growth factor 23 (FGF23). Parallel to the modulating effect of adipokines on bone turnover, certain bone proteins, such as osteocalcin and sclerostin, play a counter-regulatory role on energy metabolism, probably in an attempt to ensure its high energy requirement for bone turnover. In this crosstalk between bone and other tissues, especially with adipose tissue, canonical Wnt/β-catenin signaling is involved and therefore, sclerostin, an osteocyte derived protein that inhibits this signalling, emerges as a potential biomarker. Furthermore, its involvement in diverse pathologic conditions supports sclerostin as a therapeutic target, with an anti-sclerostin antibody recently approved in our country for the treatment of osteoporosis. This review addresses the endocrine nature of bone, the role of osteocalcin, and specially, the regulatory and modulatory role of sclerostin on bone turnover and energy homeostasis through its inhibitory effect on canonical Wnt/β-catenin signaling, as well as its potential utility as a biomarker.
... If RANKL binds to its receptor, RANK, which is expressed on the surface of osteoclast precursor cells, this binding triggers signaling pathways that activate osteoclastogenesis and leads to the differentiation of osteoclast precursors into mature osteoclasts. Furthermore, RANKL not only acts as a factor inducing osteoclast differentiation but also serves as a ligand for osteoprotegerin (OPG), which serves as an inhibitor of osteoclastogenesis [52]. ...
... If RANKL binds to its receptor, RANK, which is expressed on the surface of osteoclast precursor cells, this binding triggers signaling pathways that activate osteoclastogenesis and leads to the differentiation of osteoclast precursors into mature osteoclasts. Furthermore, RANKL not only acts as a factor inducing osteoclast differentiation but also serves as a ligand for osteoprotegerin (OPG), which serves as an inhibitor of osteoclastogenesis [52]. Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also known as GRP48): ...
... LGR4 also activates the canonical Wnt/β-catenin signaling pathway, which is essential for osteoblastogenesis and bone formation. When LGR4 is deleted or knocked out in mice, embryonic bone formation is delayed, impaired differentiation and mineralization of osteoblasts occurs, and this altered bone development leads to many bone-related pathological conditions [51][52][53][54]. ...
This review focuses on understanding the macroscopic and microscopic characteristics of bone tissue and reviews current knowledge of its physiology. It explores how these features intricately collaborate to maintain the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a pivotal role in shaping not only our physical framework but also overall health. In this work, a comprehensive exploration of microscopic and macroscopic features of bone tissue is presented.
... El incremento neto en el número y actividad osteoclástica, condiciona un aumento de la resorción ósea mediante la secreción de ácido y enzimas líticas (fosfatasa ácida tartrato resistente y catepsina K) que degradan el compartimento extracelular. En este proceso de resorción los osteoclastos liberan asímismo, diversos factores que estimulan la formación ósea (BMP6, WNT10B) o que participan en la respuesta inmune (clastoquinas) [11]. ...
... osteomorfos para formar osteoclastos explicaría, en parte, el incremento del riesgo de fractura ocasionado tras la suspensión del Denosumab (anti-RANKL que emula a la OPG). La expresión de OPG está regulada por diversos factores; se incrementa por citoquinas (TNFalfa, IL1, IL18 TGFbeta), proteínas morfogénicas (BMPs) y hormonas esteroideas (17beta estradiol) y disminuye por los glucocorticoides, la PTH y la prostaglandina E2 [11]. ...
Resumen
El hueso es mucho más que un reservorio de calcio y fósforo. Su disposición lacuno-canalicular ofrece una importante vía de intercambio con la circulación y actualmente, el esqueleto se considera un gran órgano endocrino, con acciones que van más allá del control del balance fosfocálcico mediado por el factor fibroblástico 23 (FGF23). Paralelamente al efecto modulador de las adipoquinas sobre el remodelado óseo, diversas proteínas óseas, como la osteocalcina y la esclerostina, ejercen cierta acción contra-reguladora sobre el metabolismo energético, posiblemente en un intento de asegurar los enormes requerimientos energéticos del remodelado. En esta interacción del hueso con otros tejidos, especialmente el adiposo, participa la señalización canónica Wnt/β-catenina y por ello la esclerostina, una proteína osteocítica que inhibe esta señalización, emerge como un potencial biomarcador. Es más, su participación en diversas patologías le posiciona como diana terapéutica, existiendo un anticuerpo anti-esclerostina, recientemente aprobado en nuestro país para el tratamiento de la osteoporosis. Esta revisión aborda el carácter endocrino del hueso, el papel de la osteocalcina y, especialmente, el papel regulador y modulador de la esclerostina sobre remodelado óseo y la homeóstasis energética a través de su interacción con la señalización canónica Wnt/β-catenina, así como su potencial utilidad como biomarcador.
... The ratio of RANKL and OPG is defined as a biomarker of bone health. In fact, the RANKL/OPG ratio is a useful tool for determining the extent of bone remodeling [20]. They induce RANKL expression in osteoblasts and MSCs, and increase RANK expression in osteoclast precursors, leading to osteoclast hyperactivation [21]. ...
Aging is an inevitable process of our civilization. Since ancient times, scientists have tried to solve the mystery of aging. The research continues to this day. The most common diseases of old age are disorders of the musculoskeletal system. Among them, osteoporosis continues to occupy the third place in the structure of overall morbidity and mortality. Such statistical data make us think about the search for a possible cause of the disease at the molecular level. The purpose of this study was to analyze the literature data on modern directions of osteoporosis treatment, including stem-cells based bioregenerative medicine. An analytical review of literature data was conducted using the information analysis of Medline (PubMed), Web of Science and Scopus databases, Google Scholar and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2018 to 2022 using the keywords “osteoporosis”, bioregenerative therapy”, “stem cell therapy”. Recent results of preclinical experimental studies have shown the effectiveness of the introduction of new bioregenerative technologies. In particular, the use of mesenchymal stem cells, exosomes and miRNAs. Preclinical studies on MSC transplantation in the treatment of osteoporosis indicate an increase in osteogenic differentiation, an increase in BMD. Exosomes also may play multiple roles in the treatment of osteoporosis: improving the disbalance between osteoclasts and osteoblasts, structural modification of exosomes and transmitters’ drug function. The promotion of bone regeneration of exosomes has been shown in animal models. Exosomes with active ingredients can treat a variety of skeletal disorders including osteoporosis and osteoporotic fractures. The results of recent research of the bone disorder treatment based on stem cells therapy have shown convincing prospects for new approaches.
... [19] In multiple diseases associated with bone injuries, including fractures, OPG can enhance the bone density of cortical bone and cancellous bone, suppress bone resorption, competitively and specifically bind receptor activator of nuclear factor kappa-B ligand (RANKL), and inhibit the differentiation of osteoclasts, thereby forming a RANK/RANKL/OPG system to promote bone healing and repair. [20,21] In the early stage of fracture, the activity of osteoclasts is higher than that of osteoblasts, and the secretion of OPG is insufficient. Over time, the activity of osteoclasts gradually decreases and the number of osteoblasts increases. ...
Objectives:
This study aims to investigate the predictive value of bone morphogenetic protein-7 (BMP-7), thromboxane A2 (TXA2), and osteoprotegerin (OPG) for the prognosis of patients with distal radius fractures.
Patients and methods:
Between January 2021 and January 2022, a total of 124 patients (71 males, 53 females; mean age: 49.8±5.1 years; range, 34 to 68 years) with distal radius fractures were included in the fracture group. Healthy volunteers receiving physical examination in our hospital in the same period were included in the control group (n=50; 29 males, 21 females; mean age: 50.1±5.4 years; range, 35 to 68 years). The expressions of BMP-7, TXA2, and OPG in the peripheral blood were detected. In the fracture group, 124 patients underwent internal fixation after inclusion and followed for six months. The prognosis was evaluated based on the Gartland & Werley scoring system for wrist joint function. The factors influencing prognosis were analyzed, and the predictive values of BMP-7, TXA2, and OPG were calculated.
Results:
Age, fracture classification, early loss of palmar tilt, late loss of palmar tilt, time to return to exercise after surgery, BMP-7, TXA2, and OPG were all factors influencing the prognosis (p<0.05). For predicting the prognosis, the area under the ROC curve of BMP-7 + TXA2 + OPG (0.928) was significantly larger than those of BMP-7 (0.810), TXA2 (0.856) and OPG (0.823) alone, and BMP-7 + TXA2 + OPG had the highest predictive efficiency. The BMP-7 was negatively correlated with TXA2 (r=-0.471), but positively correlated with OPG (r=0.437).
Conclusion:
The combined detection of BMP-7, OPG, and TXA2 is highly valuable for predicting the prognosis of patients with distal radius fractures.
... [24] Moreover, FGF23 has been found to negatively regulate osteogenesis and mineralization, and several pathways, such as the OPG/ RANKL, ERK1/2 (extracellular signal-related kinases 1 and 2), and OPN pathways, are associated with this role. [25][26][27] Considering the characteristics of CS patients, such as disordered osteogenesis and low BMD, we suspected that FGF23 might play a role in CS. ...
Background:
Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23.
Methods:
We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.
Results:
DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown.
Conclusions:
Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.
... At present, the receptor activator of nuclear factor-κB (RANK) ligand (RANKL)/osteoprotegerin (OPG) system is known as a central regulator of osteoclast differentiation and activation (Udagawa et al., 2021). OPG binds to RANKL on the surface of osteoclasts and competitively prevents RANKL from binding to RANK on the surface of the osteoclast lineage, thereby inhibiting the differentiation of precursor osteoclasts (Simonet et al., 1997;Carrillo-López et al., 2021). There is increasing evidence that excessive iron can affect not only osteoclastogenesis, but also osteoclast activity and bone resorption (Roodman, 2009;Balogh et al., 2018). ...
Postmenopausal osteoporosis is a kind of degenerative disease, also described as "invisible killer." Estrogen is generally considered as the key hormone for women to maintain bone mineral content during their lives. Iron accumulation refers to a state of human serum ferritin that is higher than the normal value but less than 1000 μg/L. It has been found that iron accumulation and osteoporosis could occur simultaneously with the decrease in estrogen level after menopause. In recent years, many studies indicated that iron accumulation plays a vital role in postmenopausal osteoporosis, and a significant correlation has been found between iron accumulation and fragility fractures. In this review, we summarize and analyze the relevant literature including randomized controlled trials, systematic reviews, and meta-analyses between January 1996 and July 2022. We investigate the mechanism of the effect of iron accumulation on bone metabolism and discuss the relationship of iron accumulation, osteoporosis, and postmenopausal fragility fractures, as well as the main clinical treatment strategies. We conclude that it is necessary to pay attention to the phenomenon of iron accumulation in postmenopausal women with osteoporosis and explore the in-depth mechanism of abnormal bone metabolism caused by iron accumulation, in order to facilitate the discovery of effective therapeutic targets for postmenopausal osteoporosis.
