Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.
An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.
Background and Aims Chronic kidney disease (CKD) is a major public health problem worldwide and refers to a wide range of disorders in bone and mineral metabolism, abnormalities of biochemical parameters and pathological calcification of the blood vessels. Vascular calcification (VC) is a common complication in CKD patients, contributes to cardiovascular disease (CVD), and associates with increased mortality and morbidity. The precise mechanism of VC in CKD is not yet fully understood. Recently discovered molecules such as osteoprotegerin (OPG), its ligand receptor activator of nuclear factor NF-κB ligand (RANKL) and RANK are not only well-known to play a crucial role in bone homeostasis, but they has also been implicated in the process of development of vascular complications However the exact role of OPG/RANKL/RANK axis in the process of VC has not been yet fully assessed. Thus, the aim of this work is to evaluate the role of OPG/RANKL/RANK axis in the process of calcification in CKD. Method Seventy two male Wistar rats weighing 260-290 g (8-weeks old) were initially divided into 6 groups containing 12 animals in each group. Rats were divided into six groups: control rats (K4, K6, K8) and CKD rats (B4, B6, B8). Control group rats received standard diet, whereas CKD rats were fed a low adenine – diet containing 0.3 % adenine, 1.0 % Ca, 1.2 % Pi through 4 (K4, B4), 6 (K6, B6) and 8 (K8, B8) weeks. Subsequently, CKD and control rats were sacrificed at weeks 4 (n=24), 6 (n=24) and 8 (n=24). One day before being killed, the rats were placed in metabolic cages for 24-hour urine collection. Thereafter, the rats were anesthetized and samples of blood, as well as aortas were collected. Next, the OPG, RANKL, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D3 1,25(OH)2D3 concentrations were determined using appropriate ELISA kits. Then the sRANKL/OPG ratio was calculated. The OPG, RANK and RANKL gene expression was assessed using real-time PCR (RT-PCR). The VC was quantified by measurement of the arterial calcium (Ca) and phosphate (Pi) content using flame atomic absorption. Serum levels of urea nitrogen, creatinine, uric acid, Ca, Pi and urinary levels of creatinine, Ca and Pi were measured. Results There was a progressive increase in serum urea nitrogen, creatinine, uric acid and PTH of CKD rats in comparison to control values. We also observed significantly decreased levels of 25(OH)D, 1,25(OH)2D and serum Ca. Total Ca content in the aorta was significantly increased in CKD rats in comparison with control group, whereas total Pi content in the aorta was significantly increased only in B8 group in comparison to appropriate controls. There were no differences in serum OPG and sRANKL levels between CKD and control rats. In contrast, we observed decreased OPG, RANKL and RANK gene expression in a B4 group in comparison to appropriate controls, whereas in a B6 group we noticed increased OPG, RANKL and decreased RANK gene expression. B8 group revealed increased RANKL and RANK gene expression, but there were no differences in OPG gene expression between CKD rats and control group. Furthermore, we observed positive correlations between serum sRANKL and OPG and RANK gene expression. Ca and P content in the aorta inversely corelated with RANKL gene expression, whereas positively with OPG gene expression. Serum 25(OH)D concentrations correlated inversely with Ca in aorta. PTH was positively correlated with serum RANKL and OPG and gene expression these cytokines. Conclusion Our results suggest that OPG/RANK/RANKL axis may be involved in the process of vascular calcification in chronic kidney disease. However, its role and evaluation of precise mechanism in this field requires further evaluation.
Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.
Background and Aims Chronic kidney disease - mineral bone disorder (CKD–MBD) is one of the major clinical complications in patients with chronic kidney disease (CKD). Bone remodeling has been suggested to play a fundamental role in the maintenance of skeletal integrity via a balance between the bone formation/resorption process. The parathyroid hormone (PTH) is a key hormone controlling bone metabolism. PTH is known to affect bone with a net catabolic and anabolic effect but the mechanisms responsible for these differing effects are poorly understood. Previously, we demonstrated the distinct effect of mild degree of CKD on trabecular and cortical bone strength in rapidly growing rats (Pawlak et al. PlosOne, 2016). The aim of the present study was to evaluate the effect of endogenous PTH, its receptor PTH1R and activating transcription factor 4 (ATF4) – the major regulators of the anabolic PTH response in osteoblasts on bone remodeling and growth of young rats with experimental CKD. Method Four-week old Wistar male rats were divided into 2 groups: with CKD induced by surgical 5/6 subtotal nephrectomy, and sham-operated (CON). After one (CON-1; CKD-1) and three months (CON-3; CKD-3) of the surgery the femurs were collected and their lengths were measured. The activity of alkaline phosphatase (ALP), a bone formation marker, and tartrate-resistant acid phosphatase (TRACP5b) reflecting bone resorption were determined in homogenates from trabecular and cortical left femurs. The expression of PTH1R and ATF4 gene was determined by QRT-PCR in right femurs. Serum PTH was analyzed using ELISA kit. Computations were performed using Statistica ver.10 computer software. Results Serum PTH was increased in CKD-3 compared to CKD-1, moreover the slight increase in PTH levels was noted in CKD-3 compared to appropriate controls (both p<0.05). The activity of ALP and TRACP5b in trabecular bone tissue were significantly lower in CKD-3 compared to CKD-1 rats (p<0.01 and p<0.05; respectively). There was a strong positive correlation between ALP and TRACP5b in this bone region (R =0.624, p =0.002), whereas both ALP and TRACP5b were inversely related to serum PTH (R = -0.534, p =0.012 and R = -0.636, p =0.002; respectively). The activity of TRACP5b in cortical bone tissue was significantly higher in CKD-3 compared to CKD-1 group (p<0.05), and it was positively associated with PTH levels (R =0.597, p =0.004). There was no difference in ALP activity between the studied groups, and ALP was not associated with TRACP5b in this bone region. The expression of ATF4 and PTH1R genes was significantly increased in the CKD-3 group compared with the appropriate control (p<0.01 and p<0.05; respectively) and with the CKD-1 group (p<0.05 and p<0.01; respectively). The expression of ATF4 was inversely correlated with ALP and TRACP5b in trabecular bone (R = -0.534, and R = -0.528, both p<0.05), whereas it was positively related to TRACP5b in cortical bone region (R =0.418, p<0.05). The femoral length was significantly increased during 3-month of CKD development (p<0.000), and it was positively associated with PTH levels (R =0.571, p =0.007), cortical TRACP5b activity (R =0.609, p =0.002) and tended to be related with ATF4 gene expression (R =0.409, p =0.065). In contrast, the femoral length was inversely related to ALP activity in trabecular bone tissue (R= -0.656, p =0.0007). Conclusion The endogenous PTH, through PTH1R/ATF4 axis, inhibited trabecular bone remodeling. In contrary, PTH/PTH1R/ATF4 system intensified bone resorption in cortical bone region. This opposite effect of PTH on bone remodeling was associated with the intensification of growth process in the long bones of young rats with CKD.
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