Bone-vascular Axis Research Articles

The Bone-Vascular Axis in Chronic Kidney Disease: From Pathophysiology to Treatment.

This review aims to describe the pathogenic factors involved in bone-vessel anomalies in CKD which are the object of numerous experimental and clinical research. Knowledge on the pathophysiological mechanisms involved in the regulation of vascular calcification and mineral-bone disorders is evolving. Specific bone turnover anomalies influence the vascular health while recent studies demonstrate that factors released by the calcified vessels also contribute to bone deterioration in CKD. Current therapies used to control mineral dysregulations will impact both the vessels and bone metabolism. Available anti-osteoporotic treatments used in non-CKD population may negatively or positively affect vascular health in the context of CKD. It is essential to study the bone effects of the new therapeutic options that are currently under investigation to reduce vascular calcification. Our paper highlights the complexity of the bone-vascular axis and discusses how current therapies may affect both organs in CKD.

Biomimetic Grapefruit-Derived Extracellular Vesicles for Safe and Targeted Delivery of Sodium Thiosulfate against Vascular Calcification.

As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. In vitro, the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.

Cardioprotective function of sclerostin by reducing calcium deposition, proliferation, and apoptosis in human vascular smooth muscle cells

BackgroundSclerostin is an inhibitor of the Wnt/b-catenin pathway, which regulates bone formation, and can be expressed in vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease (CVD) and increased serum and tissue expression of sclerostin. However, whether the role of sclerostin is detrimental or protective in the development of CVD is unknown. Therefore, our aims are to determine the level of sclerostin in T2D patients with/without CVD and in controls, both at serum and vascular tissue, and to analyze the role of sclerostin in VSMCs under calcified environments.MethodsCross-sectional study including 121 controls and 139 T2D patients with/without CVD (48/91). Sclerostin levels in serum were determined by ELISA, and sclerostin expression was analyzed by RT-qPCR and immunohistochemistry in calcified and non-calcified artery of lower limb from T2D patients (n = 7) and controls (n = 3). In vitro experiments were performed in VSMCs (mock and sclerostin overexpression) under calcifying conditions analyzing the sclerostin function by determination of calcium and phosphate concentrations, and quantification of calcium deposits by Alizarin Red. Proliferation and apoptosis were analyzed by MTT assay and flow cytometry, respectively. The regulation of the expression of genes involved in bone metabolism was determined by RT-qPCR.ResultsA significant increase in serum sclerostin levels in T2D patients with CVD compared to T2D patients without CVD and controls (p < 0.001) was observed. Moreover, higher circulating sclerostin levels were independently associated with CVD in T2D patients. Increased sclerostin expression was observed in calcified arteries of T2D patients compared to non-calcified arteries of controls (p = 0.003). In vitro experiments using VSMCs under calcified conditions, revealed that sclerostin overexpression reduced intracellular calcium (p = 0.001), calcium deposits (p < 0.001), cell proliferation (p < 0.001) and promoted cell survival (p = 0.015). Furthermore, sclerostin overexpression exhibited up-regulation of ALPL (p = 0.009), RUNX2 (p = 0.001) and COX2 (p = 0.003) and down-regulation of inflammatory genes, such as, IL1β (p = 0.005), IL6 (p = 0.001) and IL8 (p = 0.003).ConclusionsSclerostin could play a protective role in the development of atherosclerosis in T2D patients by reducing calcium deposits, decreasing proliferation and inflammation, and promoting cell survival in VSMCs under calcifying conditions. Therefore, considering the bone-vascular axis, treatment with anti-sclerostin for bone disease should be used with caution.Graphical

Vascular calcification in peritoneal dialysis patients and its association with bone-derived molecules and bone histomorphometry

IntroductionData regarding vascular calcification (VC) in contemporary peritoneal dialysis (PD) patients is scarce. Bone–vascular axis has been demonstrated in hemodialysis (HD). However, studies showing the link between bone disease and VC in PD patients are lacking. The role of sclerostin, dickkopf-related protein 1 (DKK-1), receptor activator for nuclear factor kB ligand and osteoprotegerin (OPG) in VC in PD remains to clarify. Materials and methodsBone biopsy was performed in 47 prevalent PD patients with histomorphometric analysis. Patients were submitted to pelvis and hands X-ray to evaluate VC using the Adragão score (AS). Relevant clinical and biochemical data was collected. ResultsThirteen patients (27.7%) had positive AS (AS≥1). Patients with VC were significantly older (58.9 vs. 50.4 years, p=0.011), had a lower dialysis dose (KT/V 2.0 vs. 2.4, p=0.025) and a higher glycosylated hemoglobin (7.2 vs. 5.4%, p=0.001). There was not any laboratorial parameter of mineral and bone disease used in clinical practice different between patients with or without VC. All diabetic patients had VC but only 8.1% of non-diabetic had VC (p<0.001). Patients with VC showed significantly higher erythrocyte sedimentation rate (ESR) (91.1 vs. 60.0mm/h, p=0.001), sclerostin (2250.0 vs. 1745.8pg/mL, p=0.035), DKK-1 (1451.6 vs. 1042.9pg/mL, p=0.041) and OPG levels (2904.9 vs. 1518.2pg/mL, p=0.002). On multivariate analysis, only ESR remained statistically significant (OR 1.07; 95% CI 1.01–1.14; p=0.022). Bone histomorphometric findings were not different in patients with VC. There was no correlation between bone formation rate and AS (r=−0.039; p=0.796). ConclusionThe presence of VC was not associated with bone turnover and volume evaluated by bone histomorphometry. Inflammation and diabetes seem to play a more relevant role in VC in PD.

Vascular calcification in peritoneal dialysis patients and its association with bone-derived molecules and bone histomorphometry

IntroductionData regarding vascular calcification (VC) in contemporary peritoneal dialysis (PD) patients is scarce. Bone–vascular axis has been demonstrated in hemodialysis (HD). However, studies showing the link between bone disease and VC in PD patients are lacking. The role of sclerostin, dickkopf-related protein 1 (DKK-1), receptor activator for nuclear factor kB ligand and osteoprotegerin (OPG) in VC in PD remains to clarify. Materials and methodsBone biopsy was performed in 47 prevalent PD patients with histomorphometric analysis. Patients were submitted to pelvis and hands X-ray to evaluate VC using the Adragão score (AS). Relevant clinical and biochemical data was collected. ResultsThirteen patients (27.7%) had positive AS (AS≥1). Patients with VC were significantly older (58.9 vs. 50.4 years, p=0.011), had a lower dialysis dose (KT/V 2.0 vs. 2.4, p=0.025) and a higher glycosylated hemoglobin (7.2 vs. 5.4%, p=0.001). There was not any laboratorial parameter of mineral and bone disease used in clinical practice different between patients with or without VC. All diabetic patients had VC but only 8.1% of non-diabetic had VC (p<0.001). Patients with VC showed significantly higher erythrocyte sedimentation rate (ESR) (91.1 vs. 60.0mm/h, p=0.001), sclerostin (2250.0 vs. 1745.8pg/mL, p=0.035), DKK-1 (1451.6 vs. 1042.9pg/mL, p=0.041) and OPG levels (2904.9 vs. 1518.2pg/mL, p=0.002). On multivariate analysis, only ESR remained statistically significant (OR 1.07; 95% CI 1.01–1.14; p=0.022). Bone histomorphometric findings were not different in patients with VC. There was no correlation between bone formation rate and AS (r=−0.039; p=0.796). ConclusionThe presence of VC was not associated with bone turnover and volume evaluated by bone histomorphometry. Inflammation and diabetes seem to play a more relevant role in VC in PD.

Coexistence of bone and vascular disturbances in patients with endogenous glucocorticoid excess

PurposeBone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. MethodsWe included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. ResultsPatients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = −0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. ConclusionIn endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

Osteogenic Circulating Endothelial Progenitor Cells are Associated with Vascular Aging of the Large Arteries in Rheumatoid Arthritis

Background and AimRheumatoid arthritis is associated with both abnormal bone metabolism and accelerated vascular aging but a mechanistic link was lacking. This study aims to investigate the role of osteocalcin (OCN)-expressing circulating endothelial progenitor cells (EPCs) in vascular aging, as determined by arterial calcifications in rheumatoid arthritis.MethodsWe performed flow cytometry studies in 145 consecutive patients with rheumatoid arthritis to determine osteogenic circulating levels of OCN-positive (OCN+) CD34+KDR+ and OCN+CD34+ versus conventional early EPC CD34+CD133+KDR+. Total calcium load of the thoracic aorta (ascending plus descending) and the carotid arteries were assessed by non-contrast computed tomography (CT) and contrast CT angiography.ResultsOsteogenic EPCs OCN+CD34+KDR+ (P = 0.002) and OCN+CD34+ (P = 0.001), together with clinical parameters of age, history of hypertension, systolic blood pressure, serum levels of triglycerides, HbA1c and creatinine, use of leflunomide and brachial-ankle pulse-wave velocity (all P < 0.05), were associated with the clustered presence of aortic and carotid calcification. Multivariable analyses revealed that circulating OCN+CD34+KDR+ (B = 14.4 [95% CI 4.0 to 24.8], P = 0.007) and OCN+CD34+ (B = 9.6 [95% CI 4.9 to 14.3], P < 0.001) remained independently associated with increased aortic calcium load. OCN+CD34+ EPC (B = 0.8 [95% CI 0.1 to 1.5], P = 0.023), but not OCN+CD34+KDR+ EPC (B = 1.2 [95% CI −0.2 to 2.6], P = 0.09), was further independently associated with carotid calcium load. In comparison, conventional early EPC CD34+CD133+KDR+ had no significant association with aortic or carotid calcium load (P = 0.46 and 0.88, respectively).ConclusionCirculating level of osteogenic EPC is associated with increased vascular aging in terms of calcification of the large arteries in patients with rheumatoid arthritis. The findings may suggest a role of the bone-vascular axis underlying vascular aging in rheumatic diseases. Further research is needed to characterize the mechanistic links and basis of these observations.

A study of bone–vascular axis in health and disease

ObjectivesThe aim was to study bone–vascular axis in health and disease.Data sourcesMedline databases (PubMed and MedScape) and all materials available in the internet were searched. The search was performed in September 2021.Study selectionThe initial search presented 120 articles. The number of studies that met the inclusion criteria was 21. The articles included both sexes and patients with bone–vascular disease.Data extractionIf the studies did not fulfill the inclusion criteria, they were excluded. Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest.Data synthesisSignificant data were collected. Then a structured review was performed.FindingIn total, 21 potentially relevant publications were included; it was found that cardiovascular and bone disease are pathophysiologically interrelated.ConclusionsCardiovascular and bone disease are pathophysiologically interrelated, even though a full understanding of the mechanisms underlying this relationship is still lacking. A better understanding of the biological link between the two processes could lead to the development of new compounds that act on both vessels and bone. Meanwhile, it would seem reasonable to consider cardiovascular disease screening in patients with advanced bone demineralization, as well as careful monitoring for signs and symptoms of cardiovascular disease in chronic kidney disease patients.

Low bone mineral density and coronary artery disease: A systematic review and meta-analysis.

Coronary artery disease (CAD) and osteoporosis both cause significant morbidity and mortality. Recent interest in inflammation and the bone-vascular axis suggests a mechanistic link between the two conditions. This review and meta-analysis was conducted to examine the potential association between low bone mineral density (BMD) and CAD in adults. Two authors searched for studies that examined the association between low BMD and CAD. Risk of bias assessment was conducted using the modified Newcastle Ottawa score. Ten studies were selected from the 2258 unique records identified. Pooled analysis showed a significant association between low BMD and CAD (OR 1.65, 95%CI 1.37–2.39, p < 0.01). Subgroup analysis investigating males and females separately was not significant. The subgroup analyses looking for any differences across geographic locations and differences between coronary imaging modalities were also negative. Studies with adjusted ORs (n = 4) were also pooled (OR 3.01, 95%CI 0.91–9.99, p = 0.07). Low BMD is associated with CAD; however, it is unclear whether this result is confounded by common risk factors given the heterogeneity between study populations and methodologies. Further large-scale epidemiological studies are required.

MO473INTERACTION OF SCLEROSTIN AND OSTEOPROTHERIN IN THE DEVELOPMENT OF VASCULAR CALCIFICATIONS AT STAGE 3-5 OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims: Background and Aims: . Vascular calcification (VC) due to bone-mineral metabolism disorders is a predictor of high cardiovascular mortality in patients with late-stage chronic kidney disease (CKD) . The established bone-vascular axis in CKD, which relates to interactions between changes in the bone and vascular systems that have similar mechanisms, allows bone metabolism inhibitors to act as potential risk factors for VC. Morphogenetic protein osteoprotegerin (OPG) and glycoprotein sclerostin are opposite inhibitors of bone metabolism: OPG inhibits osteoclastogenesis, sclerostin has an inhibitory effect on osteoblastogenesis. Although both proteins are recognized as high-risk factors for remodeling the heart and large arteries in patients with CKD, the mechanisms and possibilities for correcting these changes are not fully clear. of the study was to investigate the mechanisms of the relationship between OPG and sclerostin in the development of cardiovascular complications due to calcification of the aorta and large arteries in the late stages of CKD. Method: Method The cross-sectional study included 105 patients with stage 3-5 CKD [49 men; 64.0 (23.0-76.0)years]. The glomerular filtration rate determined using the CKD-EPI equation was 38.4 (8.6–92.3) ml / min / 1.73 m2. The general clinical examination included assessment of hematopoiesis (hemoglobin, hematocrit, ferritin and transferrin), determination of total protein and albumin levels, cholesterol, electrolytes (sodium, potassium) in the blood, and indicators of nitrogen metabolism (creatinine, urea). Parameters of bone-mineral metabolism – parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase of blood serum-were evaluated. The level of morphogenetic protein OPG and glycoprotein sclerostin was determined using commercial ELISA kit from Biomedica (Austria) by enzyme immunoassay. The morphofunctional features of the aorta and large arteries were studied by duplex scanning using the Doppler effect. We determined the peak systolic velocity of blood flow in the aortic arch (Vps-peak systolic velocity) , which indirectly indicates the state of the aortic wall and its lumen. Echocardiography with Doppler imaging was performed on the "ALOKA 4000" device. The LV myocardial mass index (LVMI), LV hypertrophy variants, LV systolic and diastolic function were determined. Results Cardiovascular damage, which manifests itself in the form of various variants of left ventricular hypertrophy, aortic rigidity, arteriosclerosis and vascular calcification, and directly correlated with the severity of renal failure, was detected in 86% of the examined patients with stage 3-5 CKD. The level of OPG and sclerostin in the blood serum increased with the progression of renal failure from the 3rd to the 5th. The main associations with Vps changes were high OPG levels [OR = 2.39 95% confidence interval (95% CI) (1.34–4.86) for levels ranging from 5.98 to 9.26 pmol / L and OR = 5.54 95% CI (2.64–13.5) for levels ≥9.26 pmol / L; P &amp;lt;0.0001] and high sclerostin levels [OR = 2.64 95% CI (1.42–5.16) for levels ranging from 0.744 to 1.211 ng / ml and OR = 3.69 95% CI (1.76–7.31) for a level ≥1.211 ng / ml; P = 0.0001]. Thus, the logistic regression model showed that the risk of aortic calcification was significantly increased when both OPG (≥5.98 pmol / L) and sclerostin (≥0.744 ng / ml) levels were high [ uncorrected model: OR = 11.93 (4.54–25.2); P &amp;lt;0.0001; on the model adjusted for generally recognized cardiovascular disease risk factors: OR= 5.55 (1.43–1914); P = 0.02]. Conclusion The results suggest that bone metabolism inhibitors, OPG and sclerostin, are independently associated with aortic calcification with potential additive effects in patients with stage 3-5 CKD. The risk of vascular calcification was significantly increased when OPG and sclerostin levels were high

Role of the RANK/RANKL/OPG and Wnt/β-Catenin Systems in CKD Bone and Cardiovascular Disorders.

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 in CKD patients requires a better understanding of the increasing complex interactions among the main modulators of the bone-vascular axis. Serum parathyroid hormone (PTH), phosphorus (P), calcium (Ca), fibroblast growth factor 23 (FGF23), calcidiol, calcitriol and Klotho are involved in this axis interact with RANK/RANKL/OPG system and the Wnt/β-catenin pathway. The RANK/RANKL/OPG system controls bone remodeling by inducing osteoblast synthesis of RANKL and downregulating OPG production and it is also implicated in vascular calcification. The complexity of this system has recently increased due the discovery of LGR4, a novel RANKL receptor involved in bone formation, but possibly also in vascular calcification. The Wnt/β-catenin pathway plays a key role in bone formation: when this pathway is activated, bone is formed, but when it is inhibited, bone formation is stopped. In the progression of CKD, a downregulation of the Wnt/β-catenin pathway has been described which occurs mainly through the not coincident elevations of sclerostin, Dickkopf1 (Dkk1) and the secreted Frizzled Related Proteins (sFRPs). This review analyzes the interactions of PTH, P, Ca, FGF23, calcidiol, calcitriol and Klotho with the RANKL/RANKL/OPG system and the Wnt/β-catenin, pathway and their implications in bone and cardiovascular disorders in CKD.

Shuxuetong injection simultaneously ameliorates dexamethasone-driven vascular calcification and osteoporosis.

Osteoporosis (OP) and vascular calcification (VC) share a number of common risk factors, pathophysiological mechanisms and etiology, which are known as bone-vascular axis. The present study aimed to investigate the effects of Shuxuetong (SXT) injection on VC and osteoporosis. A rat model of VC and osteoporosis was induced by dexamethasone (DEX; 1 mg/kg/day for 4 weeks, intramuscularly). Simultaneously, 0.6 ml/kg/day SXT was intraperitoneally injected. Compared with control rats, DEX induced significantly more VC and OP, as determined by increased calcium deposition and alkaline phosphatase activity in the aorta, disturbed structure, decreased levels of cortical bone thickness and trabecular bone area, and increased apoptosis in the bone. SXT injection ameliorated DEX-induced VC and osteoporosis; furthermore, the osteoblastic differentiation of vascular smooth muscle cells and the activation of endoplasmic reticulum stress in the DEX group was also prevented by SXT injection. Compared with control rats, protein expression levels of sclerostin, a crucial crosslink of the bone-vascular axis, were significantly increased in the aorta and bone of rats with DEX, which was also attenuated by SXT injection. Thus, the present study suggested that SXT injection could ameliorate both VC and OP, and may be mediated by the regulation of sclerostin. The present study may provide the basis a novel strategy for the prevention and treatment of VC and OP, which emerge as side-effects of glucocorticoids.

Low Bone Mineral Density and Coronary Artery Disease. A Meta-analysis

Coronary Artery Disease (CAD) and Osteoporosis both cause significant morbidity and mortality. Recent interest in the bone-vascular axis suggests a mechanistic link between the two conditions. The goal of this meta-analysis is to examine the potential association between low bone mineral density (BMD) and CAD in adults.

Bone mineral density and mortality in end-stage renal disease patients.

Osteoporosis characterized by low bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) is common among end-stage renal disease (ESRD) patients and associates with high fracture incidence and high all-cause mortality. This is because chronic kidney disease-mineral bone disorders (CKD-MBDs) promote not only bone disease (osteoporosis and renal dystrophy) but also vascular calcification and cardiovascular disease. The disturbed bone metabolism in ESRD leads to ‘loss of cortical bone’ with increased cortical porosity and thinning of cortical bone rather than to loss of trabecular bone. Low BMD, especially at cortical-rich bone sites, is closely linked to CKD-MBD, vascular calcification and poor cardiovascular outcomes. These effects appear to be largely mediated by shared mechanistic pathways via the ‘bone–vascular axis’ through which impaired bone status associates with changes in the vascular wall. Thus, bone is more than just the scaffolding that holds the body together and protects organs from external forces but is—in addition to its physical supportive function—also an active endocrine organ that interacts with the vasculature by paracrine and endocrine factors through pathways including Wnt signalling, osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand system and the Galectin-3/receptor of advanced glycation end products axis. The insight that osteogenesis and vascular calcification share many similarities—and the knowledge that vascular calcification is a cell-mediated active rather than a passive mineralization process—suggest that low BMD and vascular calcification (‘vascular ossification’) to a large extent represent two sides of the same coin. Here, we briefly review changes of BMD in ESRD as observed using different DXA methods (central and whole-body DXA) at different bone sites for BMD measurements, and summarize recent knowledge regarding the relationships between ‘low BMD’ and ‘fracture incidence, vascular calcification and increased mortality’ in ESRD patients, as well as potential ‘molecular mechanisms’ underlying these associations.

The Role of Gut Dysbiosis in the Bone-Vascular Axis in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk of bone mineral density loss and vascular calcification. Bone demineralization and vascular mineralization often concur in CKD, similar to what observed in the general population. This contradictory association is commonly referred to as the ‘calcification paradox’ or the bone–vascular axis. Mounting evidence indicates that CKD-associated gut dysbiosis may be involved in the pathogenesis of the bone–vascular axis. A disrupted intestinal barrier function, a metabolic shift from a predominant saccharolytic to a proteolytic fermentation pattern, and a decreased generation of vitamin K may, alone or in concert, drive a vascular and skeletal pathobiology in CKD patients. A better understanding of the role of gut dysbiosis in the bone–vascular axis may open avenues for novel therapeutics, including nutriceuticals.

Bone Mineral Density and Aortic Calcification: Evidence for a Bone-vascular Axis After Kidney Transplantation.

Chronic kidney disease mineral and bone disorders (CKD-MBD) and vascular calcification are often seen in kidney transplantation recipients (KTR). This study focused on the bone-vascular axis hypothesis, the pathophysiological mechanisms driving both bone loss and vascular calcification, supported by an association between lower bone mineral density (BMD) and higher risk of vascular calcification. KTR referred for a dual-energy X-ray absorptiometry procedure within 6 mo after transplantation were included in a cross-sectional study (2004-2014). Areal BMD was measured at the proximal femur, and abdominal aortic calcification (AAC) was quantified (8-points score) from lateral single-energy images of the lumbar spine. Patients were divided into 3 AAC categories (negative-AAC: AAC 0; low-AAC: AAC 1-3; and high-AAC: AAC 4-8). Multivariable-adjusted multinomial logistic regression models were performed to study the association between BMD and AAC. We included 678 KTR (51 ± 13 y old, 58% males), 366 (54%) had BMD disorders, and 266 (39%) had detectable calcification. High-AAC was observed in 9%, 11%, and 25% of KTR with normal BMD, osteopenia, and osteoporosis, respectively (P < 0.001). Higher BMD (T-score, continuous) was associated with a lower risk of high-AAC (odds ratio 0.61, 95% confidence interval 0.42-0.88; P = 0.008), independent of age, sex, body mass index, estimated glomerular filtration rate, and immunosuppressive therapy. KTR with normal BMD were less likely to have high-AAC (odds ratio 0.24, 95% confidence interval 0.08-0.72; P = 0.01). BMD disorders are highly prevalent in KTR. The independent inverse association between BMD and AAC may provide evidence to point toward the existence, while highlighting the clinical and epidemiological relevance, of a bone-vascular axis after kidney transplantation.

Association of sclerostin with cardiovascular events and mortality in dialysis patients

Introduction Sclerostin has been reported to be a novel biomarker associated with the bone-vascular axis. In this study, we determined the relationships between serum sclerostin and all-cause mortality, the prevalence of cardiovascular events (CVEs), and coronary artery calcifications (CACs) in dialysis patients. Methods A total of 165 dialysis patients (84 hemodialysis [HD] and 81 peritoneal dialysis [PD]) were enrolled in this study. We performed multivariable linear regression analysis to test the relationships between serum sclerostin levels and demographics and clinical parameters. We also performed Cox proportional hazard regression analysis to determine independent predictors of overall survival and CVEs. Results The median serum sclerostin level was 250.9 pg/mL in dialysis patients. Kaplan–Meier analysis showed that both overall and CVE-free survival rates were significantly lower in the high serum sclerostin group (serum sclerostin level >250.9 pg/mL) compared to the low serum sclerostin group (serum sclerostin level ≤250.9 pg/mL) in patients with PD (p < 0.05). In patients with HD, only CVE-free survival rates notably declined in the high serum sclerostin group compared to the low serum sclerostin group (p = 0.029). However, serum sclerostin level was only an independent predictor of all-cause mortality and CVEs in patients with PD after adjusting for confounding factors (p < 0.05), and therefore was not an independent predictor for patients with HD (p > 0.05). Conclusions A low serum sclerostin was associated with better overall survival and lower prevalence of CVEs in patients with PD, but had no relationships in patients with HD. We found that serum sclerostin level was not correlated with CACs in either patients with HD or PD.

Role of NFATc1 in the Bone-Vascular Axis Calcification Paradox.

Nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a crucial member of the transcription factor NFAT family, is indispensable in the immune system and the morphogenesis of cardiac valves and septa and is also vital in osteoclasts and atherosclerotic calcification. Currently, osteoporosis and vascular diseases are severely hazardous to health and quality of life, and the 2 conditions always coincide with each other. The bone-vascular axis calcification paradox serves as a bridge between bone and vascular diseases, linking these 2 seemingly separate diseases, and the receptor activator of NF-κB (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) system may be the common mechanism of the bone-vascular axis calcification paradox. NFATc1 provides a new therapeutic target for bone and vascular diseases. However, the specific mechanism by which NFATc1 acts on the bone-vascular axis calcification paradox, whether NFATc1 is related to the RANK/RANKL/OPG system, and how to use NFATc1 as a therapeutic target to avoid its side effects in other systems requires further study.

Therapeutic strategy for atherosclerosis based on bone-vascular axis hypothesis.

As the world's older population grows, the disease burden of atherosclerosis is rapidly increasing, causing significant morbidity and mortality worldwide. Despite recent improvements in the control of vascular risk factors, a significant number of patients still suffer from vascular events and the progression of atherosclerosis. Aging also results in decreased bone mineral density. Since bones are a home for hematopoietic stem cells as well as reservoirs of the minerals required for vascular integrity, it is conceivable that a novel therapeutic strategy for atherosclerosis treatment can be developed by focusing on the complex interplay between bones and blood vessels. The correction of mineral dyshomeostasis, disrupted bone marrow microenvironments, and triggered inflammatory cell production provide potential therapeutic options against the atherosclerotic process. This review highlights recent advances in our understanding of the bone-vascular link and discusses new insights into treatment targets for atherosclerosis.

Bone-Vascular Axis in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk of osteoporosis and vascular calcification. Bone demineralization and vascular mineralization go often hand in hand in CKD, similar to as in the general population. This contradictory association is independent of aging and is commonly referred to as the "calcification paradox" or the bone-vascular axis. Various common risk factors and mechanisms have been identified. Alternatively, calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that favor vascular calcification. The present review focuses on emerging concepts and major mechanisms involved in the bone-vascular axis in the setting of CKD. A better understanding of these concepts and mechanisms may identify therapeutics able to target and exert beneficial effects on bone and vasculature simultaneously.