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The function of adiponectin in AIS osteopenia. Gene variation leads to the increase in plasma adiponectin which exerts its negative effect on bone metabolism via RANKL/OPG and IL6 pathway in primary osteoblast and chondrocyte in AIS osteopenia
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Abstract Background Osteopenia have been well documented in adolescent idiopathic scoliosis (AIS). Adiponectin has been shown to be inversely proportional to body mass index and to affect bone metabolism. However, the circulating levels of adiponectin and the relationship between adiponectin and low bone mass in AIS remain unclear. Methods A total...
Citations
... Receptors include Ob-Rb (long-form receptor primarily distributed in MSCs); upon binding, adiponectin can activate multiple signaling pathways and regulate the expression of related genes, contributing to the differentiation of hematopoietic stem cells (HSCs) into OCs (166). Pathways implicated include RANK/RANKL, JAK/STAT, and MAPK, promoting bone metastasis by influencing OC formation and maturation (135)(136)(137)(138)(139) (Table 1). In summary, adiponectin exerts an indirect influence on osteolytic metastasis in lung cancer primarily through modulating angiogenesis within the tumor microenvironment, participating in the regulation of OC activity, and affecting the equilibrium of bone remodeling. ...
Bone is a common site of metastasis for lung cancer. The “seed and soil” hypothesis suggests that the bone marrow microenvironment (“soil”) may provide a conducive survival environment for metastasizing tumor cells (“seeds”). The bone marrow microenvironment, comprising a complex array of cells, includes bone marrow adipocytes (BMAs), which constitute about 70% of the adult bone marrow volume and may play a significant role in tumor bone metastasis. BMAs can directly provide energy for tumor cells, promoting their proliferation and migration. Furthermore, BMAs participate in the tumor microenvironment’s osteogenesis regulation, osteoclast(OC) regulation, and immune response through the secretion of adipokines, cytokines, and inflammatory factors. However, the precise mechanisms of BMAs in lung cancer bone metastasis remain largely unclear. This review primarily explores the role of BMAs and their secreted adipokines (leptin, adiponectin, Nesfatin-1, Resistin, chemerin, visfatin) in lung cancer bone metastasis, aiming to provide new insights into the mechanisms and clinical treatment of lung cancer bone metastasis.
... Adiponectin exacerbated collagen-induced arthritis via enhancing Th17 response and prompting RANKL expression [39]. Adiponectin also had a negative effect on bone metabolism in adolescent idiopathic scoliosis osteopenia via ADR1-RANKL/OPG, a RANKL/OPG pathway activated by adiponectin receptor 1 (ADR1) [40]. ...
Background: Diabetes mellitus is an increasing global health emergency, with serious complications (including osteoporosis). Leptin and adiponectin are among the least-investigated possible contributing factors of T1D low bone mass. Methods: In this case-control cross-sectional analysis, we evaluated 40 pairs of T1D children and adolescents and controls. We evaluated body diameters and skinfolds, leptin, adiponectin, lipids and lipoproteins, bone metabolic markers and DXA parameters of BMD and fat percentage. Results: Leptin levels were comparable between groups and correlated well with body mass parameters. Adiponectin levels were found to be higher in the patient group and correlated with higher levels of HbA1c, triglycerides and s-RANKL. Conclusions: In this study, leptin levels were no different, but adiponectin levels were found to be higher in children and adolescents with T1D and correlated with diabetic metabolic derangement indices and s-RANKL in the patient group. Adiponectin can be considered a surrogate marker of T1D in young patients’ metabolic status and probably contributes to the diabetic low bone mass phenotype via activation of the RANKL/OPG metabolic pathway.
... There were 30 studies [6, 28-56] on genetic risk factors related to low BMD in children with IS, eight studies on endocrine risk factors [57][58][59][60][61][62][63][64], and 18 studies [5,[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] on lifestyle-related risk factors. A total of 10,768 participants with IS were included in the 56 included studies, consisting of 295 male patients with IS in 14 studies [30,31,33,38,40,43,44,48,51,56,[63][64][65][66]. ...
... Osteoprotegerin (OPG) is a receptor activator of nuclear factor kappa-B ligand (RANKL) decoy receptor that prevents RANKL from binding to its receptor receptor activator of nuclear factor kappa-B (RANK), preventing osteoclast development and activation [40]. Ten included studies [30,32,36,40,42,44,48,51,52,54] showed that G → C mutation in OPG gene site 1181 and T single nucleotide polymorphism in adiponectin gene site rs7639352 might be associated with low BMD. In addition, BMD in children with IS may be decreased by the knockdown or overexpression of miR-145/β-catenin via inhibiting osteocyte function. ...
... Three studies showed that low Runx2 expression might be related to low BMD [43][44][45]. G-c polymorphism at the -174 and -572 sites of the Interleukin-6 (IL-6) gene promoter was associated with low BMD, and adiponectin may be a mediator in this pathway of bone development [33,34,51]. ...
Background
Children with idiopathic scoliosis (IS) have a high risk of osteoporosis and IS with low bone mineral density (BMD) are susceptible to curve progression. This review aims to explore the risk factors of low BMD in children with IS.
Methods
Studies were retrieved from 5 databases that were published up to January 2022. Search terms are keywords in titles or abstracts, including subject headings related to “Scoliosis”, “Bone Mineral Density”, and “Risk Factors”. Observational studies on risk factors of low BMD in children with IS were enrolled in this review. The number of studies, sample size, outcome measures, research type, endocrine, and lifestyle-related factors, gene/signal pathway, and other contents were extracted for qualitative analysis.
Results
A total of 56 studies were included in this scoping review. Thirty studies involved genetic factors that may affect BMD, including the Vitamin-D receptor gene, RANK/RANKL signal pathway, the function of mesenchymal stem cells, Runx2, Interleukin-6 (IL-6), and miR-145/β-catenin pathway. Eight studies mentioned the influence of endocrine factors on BMD, and the results showed that serum levels of IL-6, leptin and its metabolites, and ghrelin in children with IS were different from the age-matched controls. In addition, there were 18 articles on lifestyle-related factors related to low BMD in children with IS, consisting of physical activity, calcium intake, Vitamin D level, and body composition.
Conclusions
Genetic, endocrine, and lifestyle-related factors might relate to low BMD and even osteoporosis in IS. To prevent osteoporosis, the effectiveness of regular screening for low BMD risk factors in children with IS needs to be investigated. Additionally, clear risk factors suggest strategies for bone intervention. Future studies should consider the effectiveness of calcium and vitamin D supplements and physical activity in BMD improvement.
... Several studies have revealed that osteopenia is related to abnormal levels of some metabolic hormones, such as estrogen, leptin, adiponectin, and ghrelin. [16][17][18][19] Some researchers have also suggested that diet and microelement intake contribute to AIS-related osteopenia. [17,20] Bone marrow stem cells (BMSCs) are progenitor cells for bone tissue and adipose tissue in marrow cavity formation. ...
... In previous studies, several hormones have been proven to be involved in AIS-related osteopenia. [16][17][18][19] Dysregulation between hormones and osteogenic cells leads to a lower osteogenic ability in AIS patients, which eventually results in bone mass loss. BMSCs are progenitor cells in skeletal tissue that have strong osteogenic and adipogenic abilities and play an important role in the balance of bone metabolism. ...
Background:
Osteopenia has been well documented in adolescent idiopathic scoliosis (AIS). Bone marrow stem cells (BMSCs) are a crucial regulator of bone homeostasis. Our previous study revealed a decreased osteogenic ability of BMSCs in AIS-related osteopenia, but the underlying mechanism of this phenomenon remains unclear.
Method:
A total of 22 AIS patients and 18 age-matched controls were recruited for this study. Anthropometry and bone mass were measured in all participants. Bone marrow blood was collected for BMSC isolation and culture. Osteogenic and adipogenic induction were performed to observe the differences in the differentiation of BMSCs between the AIS-related osteopenia group and the control group. Furthermore, a total RNA was extracted from isolated BMSCs to perform RNA sequencing and subsequent analysis.
Results:
A lower osteogenic capacity and increased adipogenic capacity of BMSCs in AIS-related osteopenia were revealed. Differences in mRNA expression levels between the AIS-related osteopenia group and the control group were identified, including differences in the expression of LRRC17, DCLK1, PCDH7, TSPAN5, NHSL2, and CPT1B. Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed several biological processes involved in the regulation of autophagy and mitophagy. The Western blotting results of autophagy markers in BMSCs suggested impaired autophagic activity in BMSCs in the AIS-related osteopenia group.
Conclusion:
Our study revealed that BMSCs from AIS-related osteopenia patients have lower autophagic activity, which may be related to the lower osteogenic capacity and higher adipogenic capacity of BMSCs and consequently lead to the lower bone mass in AIS patients.
... Previous research has investigated the genetic susceptibility to low bone mass and osteopenia reported in AIS patients. A case-control study has revealed that genetic polymorphisms in ADIPOQ are associate with AIS osteopenia through the dysregulation of ADR1-RANKL/OPG and ADR1-IL6 pathways [13]. In addition, BSML polymorphism was reported to associate with the lumbar spine bone mineral density in AIS, indicating the influence of vitamin D receptor genes [14]. ...
Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal curvature deformity that appears in the adolescent period. In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb’s angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN, CLCN1, and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN, CLCN1, and SOX8 as the most likely susceptibility genes for severe AIS.
... However, it remains unsolved whether osteoporosis or osteopenia is an individual characteristic or a general phenomenon in IS patients. Some studies showed that the low BMD in IS patients was associated with congenital genetic factors, such as defects in the RANK/RANKL, or Runx2 signal pathway, which are associated with osteopenia and osteoporosis [11,12]. Osteopenia is present in IS individuals with an abnormal RANKL/OPG ratio, but this genetic susceptibility is not common in the IS population [11]. ...
... Rights reserved. The demographic variables, outcome measures, and main results of the included studies are shown in Table 2. Eleven case-control studies [11,12,17,28,30,36,41,42,44,46,47] recruited 469 males. The body mass index (BMI) in the IS group was generally lower than that in the control group. ...
... The BMD z score is the standardized value calculated by comparison with BMD of the same age, gender, and ethnic group [29]. The BMD z score was reported in 12 case-control studies 11,12,15,16,18,19,27,29,38,42,45,47, and the pooled analysis revealed significant differences (WMD −1.191; 95% CI −1.651 to −0.732, p < 0.001; I 2 = 96.9%, p < 0.001). ...
Purpose:
Osteoporosis is a risk factor for idiopathic scoliosis (IS) progression, but it is still unclear whether IS patients have bone mineral density (BMD) loss and a higher risk of osteoporosis than asymptomatic people. This systematic review aims to explore the differences in BMD and prevalence of osteoporosis between the IS group and the control group.
Methods:
We searched 5 health science-related databases. Studies that were published up to February 2022 and written in English and Chinese languages were included. The primary outcome measures consisted of BMD z score, the prevalence of osteoporosis and osteopenia, and areal and volumetric BMD. Bone morphometry, trabecular microarchitecture, and quantitative ultrasound measures were included in the secondary outcome measures. The odds ratio (OR) and the weighted mean difference (WMD) with a 95% confidence interval (CI) were used to pool the data.
Results:
A total of 32 case-control studies were included. The pooled analysis revealed significant differences between the IS group and the control group in BMD z score (WMD -1.191; 95% CI - 1.651 to -0.732, p < 0.001). Subgroup analysis showed significance in both female (WMD -1.031; 95% CI -1.496 to -0.566, p < 0.001) and male participants (WMD -1.516; 95% CI -2.401 to -0.632, p = 0.001). The prevalence of osteoporosis and osteopenia in the group with IS was significantly higher than in the control group (OR = 6.813, 95% CI 2.815-16.489, p < 0.001; OR 1.879; 95% CI 1.548-2.281, p < 0.000). BMD measures by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography showed a significant decrease in the IS group (all p < 0.05), but no significant difference was found in the speed of sound measured by quantitative ultrasound between the two groups (p > 0.05).
Conclusion:
Both the male and female IS patients had a generalized lower BMD and an increased prevalence of osteopenia and osteoporosis than the control group. Future research should focus on the validity of quantitative ultrasound in BMD screening. To control the risk of progression in IS patients, regular BMD scans and targeted intervention are necessary for IS patients during clinical practice.
... Adiponectin has the opposite effect of leptin as it is anti-inflammatory, promotes insulin sensitivity, and its serum levels are reduced in obesity [50,51]. Moreover, one study found that AIS patients with osteopenia have higher adiponectin levels compared to those with normal BMD and to healthy controls [52]. Other known adipokines have not yet been studied in AIS, such as resistin and visfatin, but they could also be of interest as they have similar metabolic functions as leptin and adiponectin [53][54][55][56]. ...
... However, this does not appear to be the case in our study, as no association was found between adiponectin, BMI-for-age, and fat percentage. Corroborating our findings, Zhang et al. found higher plasma adiponectin levels in AIS patients than in controls [52]. However, they also found higher adiponectin levels in AIS patients with osteopenia compared to those with normal bone mass, while no such association was found in our pilot study. ...
... In contrast, there was no significant variation in OPG and RANKL expression in AIS osteoblasts. Treatment of osteoblasts with adiponectin had the opposite effect of ghrelin and rather promoted a higher RANKL/OPG ratio, which leads to an increase in bone resorption [46,52]. Higher adiponectin levels in AIS could reflect a higher RANKL/OPG ratio in osteoblasts, which could impact BMD. ...
Adolescent idiopathic scoliosis (AIS) is a three-dimensional malformation of the spine of unknown cause that develops between 10 and 18 years old and affects 2–3% of adolescents, mostly girls. It has been reported that girls with AIS have a taller stature, lower body mass index (BMI), and bone mineral density (BMD) than their peers, but the causes remain unexplained. Energy metabolism discrepancies, including alterations in adipokine and incretin circulatory levels, could influence these parameters and contribute to disease pathophysiology. This pilot study aims to compare the anthropometry, BMD, and metabolic profile of 19 AIS girls to 19 age-matched healthy controls. Collected data include participants' fasting metabolic profile, anthropometry (measurements and DXA scan), nutritional intake, and physical activity level. AIS girls (14.8 ± 1.7 years, Cobb angle 27 ± 10°), compared to controls (14.8 ± 2.1 years), were leaner (BMI-for-age z-score ± SD: −0.59 ± 0.81 vs. 0.09 ± 1.11, p = 0.016; fat percentage: 24.4 ± 5.9 vs. 29.2 ± 7.2%, p = 0.036), had lower BMD (total body without head z-score ± SD: −0.6 ± 0.83 vs. 0.23 ± 0.98, p = 0.038; femoral neck z-score: −0.54 ± 1.20 vs. 0.59 ± 1.59, p = 0.043), but their height was similar. AIS girls had higher adiponectin levels [56 (9–287) vs. 32 (7–74) ug/mL, p = 0.005] and lower leptin/adiponectin ratio [0.042 (0.005–0.320) vs. 0.258 (0.024–1.053), p = 0.005]. AIS participants with a Cobb angle superior to 25° had higher resistin levels compared to controls [98.2 (12.8–287.2) vs. 32.1 (6.6–73.8), p = 0.0013]. This pilot study suggests that adipokines are implicated in AIS development and/or progression, but more work is needed to confirm their role in the disease.
... Встановлено, що клітини кісток, включаючи остеобласти, остеокласти, мезенхімальні стволові клітини кісткового мозку та адипоцити, можуть синтезувати та виділяти різноманітні біоактивні речовини, такі як білки, поліпептиди, цитокіни, запальні фактори, адипокіни та утворювати екзосоми. Ці гуморальні фактори потрапляють в кровообіг і діють на дистальні органи, впливаючи тим самим на енергетичний обмін усього тіла [5][6][7][8]. Крім того, вони здатні регулювати енергетичний гомеостаз шляхом зміни чутливості різних тканин до інсуліну, харчової поведінки та функції адипоцитів [2]. Ці дані відображують новий патофізіологічний механізм розвитку дисметаболічних захворювань, таких як остеопороз, ожиріння та цукровий діабет [9][10][11]. ...
... Порушення вуглеводного обміну визначали за вмістом в крові показників інсуліну (3-25 мОд/л), глюкози натще (4,1-6,0 ммоль/л) та глікованого гемоглобіну (4,8-5,9%). Ступінь інсулінорезистентності оцінювали за допомогою моделі оцінки гомеостазу (HOMA-IR) [8]. ...
Background. Current data suggest that bone tissue produces hormonally active factors - modulators of metabolic processes throughout the body. The most significant osteoproteins is osteocalcin, the non-collagen structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream during the resorption of bone tissue. Osteocalcin is involved in the regulation of energy balance, insulin secretion, peripheric insulin sensitivity, and adipocyte’s function, while being an important marker of bone remodeling. The aim of this study was to investigate the relationship between osteocalcin levels and metabolic parameters in 97 patients with type 2 diabetes over 50 years of age, in the course of pharmacotherapy using different classes of antidiabetic drugs, namely human insulin, glucagon-like peptide-1 agonists (aGLP), and sodium-glucose co-transporter 2 (SGLT2) inhibitors, depending on presence of obesity. Results. There was found the highest serum osteocalcin level in patients without obese who received a metabolically active therapy with insulin or aGLP-1, comparing to nonobese subjects of SGLT2 inhibitors therapy group. The lowest level of HbA1c and triglycerides observed in non-obese patients on the background of taking aGLP-1. Conclusion. It can be assumed that the factor determining the hypoglycemic efficacy of investigated drugs may be the pathogenesis of type 2 diabetes which depends on the degree of obesity, while the type of antidiabetic therapy has a corrective effect, probably mediated by changes in body weight and fat distribution.
... These features are thought to be related to leptin and adiponectin, 73,74 since leptin levels in patients with AIS are decreased 73,75 whereas adiponectin levels are increased. 76 The low BMI should theoretically be associated with high leptin levels, but it is low in AIS. There are several factors that can help explain this anomaly. ...
... 94 In addition, we showed that adiponectin can decrease expression of OPG and increase expression of RANKL, inducing osteoclastogenesis and bone resorption, adiponectin levels are increased in AIS patients, and via these effects on bone metabolism can contribute to the lower bone mass seen in AIS ( Figure 2). 76 There are many similarities in the mechanisms of action of leptin and adiponectin in AIS. Both can regulate the development of skeletal muscle and bone tissue. ...
Adolescent idiopathic scoliosis (AIS) is a common spinal deformity characterized by changes in the three‐dimensional structure of the spine. It usually initiates during puberty, the peak period of human growth when the secretion of numerous hormones is changing, and it is more common in females than in males. Accumulating evidence shows that the abnormal levels of many hormones including estrogen, melatonin, growth hormone, leptin, adiponectin and ghrelin, may be related to the occurrence and development of AIS. The purpose of this review is to provide a summary and critique of the research published on each hormone over the past 20 years, and to highlight areas for future study. It is hoped that the presentation will help provide a better understanding of the role of endocrine hormones in the pathogenesis of AIS.
... A study conducted by Cho DC et al. showed that androgen blocks IL-6 to promote cortical bone formation in mice (17), indicating that IL-6 expression in patients with AIS might be correlated with androgen abnormalities. In addition, numerous studies have indicated that IL-6 is closely associated with cartilage abnormalities in patients with osteoarthritis (18)(19)(20). As a member of the interleukin family, IL-6 can be secreted by many types of cells and can induce the proliferation and differentiation of many cell types. ...
... The experimental method used for qRT-PCR was based on a previously described method (18). The following primers were used in this study: 18S, ...
... Therefore, we collected facet joint tissue during surgery for IHC and WB analyses, and the results showed that AR expression and the levels of IL-6, MMP9 and MMP13 were significantly increased in the cartilage tissue of AIS patients, which might be important factors inducing abnormal development or chondrocyte degradation in patients with AIS. High levels of a number of cellular and soluble factors, including inflammatory cytokines, such as IL-6, are present in AIS cartilage (18). IL-6 causes cartilage damage by acting on both anabolic and catabolic mechanisms of cartilage physiology (27). ...
Background:
Adolescent idiopathic scoliosis (AIS) is a disease characterized by changes in the three-dimensional structure of the spine. Studies have shown that the development of AIS might be associated with genetic, biomechanics, endocrine factors and abnormal bone or cartilage development.
Methods:
Blood samples collected from 301 female patients (161 females with AIS and 140 females without AIS) were used for genotyping. Forty-eight serum samples from 161 females with AIS and 40 serum samples from 140 females without AIS were subjected to enzyme-linked immunosorbent assays (ELISAs). We also evaluated 32 facet joints (18 females with AIS and 14 females without AIS from the 301 female patients) using immunohistochemistry, Western blotting, and isolation of human primary chondrocytes, among other methods. We treated the AIS primary chondrocytes with dihydrotestosterone (DHT) to verify the relationship among androgen, the androgen receptor (AR), and its downstream pathway proteins.
Results:
The serum androgen level in the AIS group was significantly decreased (1.94±0.09 vs. 2.284±0.103) compared with that in the non-AIS (control) group. The single nucleotide polymorphism genotyping results showed that the mutation rates of rs6259 between the AIS and control groups were significantly different (G/G genotype: 48.4% vs. 42.1%, G/A genotype: 40.4% vs. 35.7%, P<0.05). The levels of interleukin (IL)-6 and metalloproteinase (MMP)-13 were increased in the cartilage of AIS patients, and these patients also exhibited decreased AR levels. The cell experiment results showed that androgen reduced the degree of abnormal cartilage development in female AIS patients through the AR/IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway.
Conclusions:
Our study provides a new perspective on the pathogenesis of AIS and indicates that decreased androgen levels in female AIS patients play a potential role in the development of AIS via the AR/IL-6/STAT3 signaling pathway.
