Increased Fibroblast Growth Factor-23 Research Articles

Free Radical Oxidation and Metabolic Processes of Cartilage and Bone Tissues in Animals with Surgical Model of Posttraumatic Osteoarthrosis

INTRODUCTION: Posttraumatic osteoarthrosis (PTOA) resulting from injuries of connective-tissue components of the joint, is accompanied by formation of free radicals activating chondro- and osteoresorption, which leads to fragmentation of biopolymers of the extracellular matrix of the joint tissues.
 AIM: To study the peculiarities of free radical oxidation and metabolic processes of cartilage and bone tissues in animals with a surgical model of PTOA of the knee joint.
 MATERIALS AND METHODS: The study was conducted on 31 rats (11 intact animals and 20 animals with PTOA model). The metabolic processes of the connective tissue were evaluated by the changes in the content of biomarkers of the cartilage (hyaluronan, aggrecan) and bone (fibroblast growth factor-23, osteprotegerin, sclerostin, osteocalcin) tissues. The condition of the free radical oxidation processes was evaluated by the level of lipid hydroperoxides, and the activity of antioxidant system by the parameters of the total antioxidant and thiol statuses.
 RESULTS: In rats with the PTOA model, an increase in cartilage tissue biopolymers aggrecan and hyaluronan (p 0.001) was noted with a negative change in the marker of bone formation (a tendency to increase in the content of osteocalcin) and markers of regulation of bone homeostasis (increased fibroblast growth factor-23, p 0.001), with a tendency to decrease in the content of osteoprotegerin and sclerostin, in comparison with intact animals of the control group. In parallel with this, an increase in lipid hydroperoxides (p 0.01) in the systemic bloodstream was detected with a decrease in the thiol status index (p 0.01) with preserved normal total antioxidant activity (p 0.05).
 CONCLUSION: The data of the conducted study evidences intensification of free radical oxidation and derangement of metabolic processes in the bone and cartilage tissues in animals with a surgical model of PTOA of the knee joint. A negative change in the metabolism of the bone tissue was manifested by the loss of balance of remodeling processes, and metabolic disorders in the cartilage tissue consisted in the destruction of its biopolymers in conditions of intensification of free radical oxidation processes and relative tension of the thiol system with the total antioxidant activity remaining within the physiological norm. The established facts are promising from the point of view of using the studied biomarkers both for the identification of pathogenetic triggers of PTOA of the knee joint, and for the determination of the direction of therapeutic measures.

The Effectiveness and Safety of Calcium Carbonate Use in Chronic Kidney Disease Patients with Normophosphatemia

Background: Patients with early and moderate stages of chronic kidney disease (CKD) have normal serum phosphate levels. Increased fibroblast growth factor-23 (FGF23) levels in these patients are responsible for maintaining normophosphatemia status by increasing the excretion of phosphate through urine. However, an increased serum FGF23 level is related to cardiomegaly, vascular calcification, CKD progression, and mortality. This study aimed to examine the effectiveness and safety of calcium carbonate use in stage 3 or 4 CKD patients with normophosphatemia. Methods: This double-blind randomized controlled trial (ClinicalTrials.gov identifier NCT03550534) included stage 3 or 4 CKD patients with normophosphatemia who visited the nephrology or endocrinology clinic at Dr. Cipto Mangunkusumo Hospital. Forty-six subjects were randomized to receive either calcium carbonate or placebo over a 12-weeks period. Urine phosphate, serum phosphate, serum calcium, and serum intact FGF23 levels were measured before and after the intervention. Results: The baseline characteristics of the two groups were similar, except for the higher prevalence of dyslipidemia in the placebo group. The CaCO3 group had shown reduced levels of FGF23 compared to the placebo group, -8.03 vs. 0.15 pg/ml respectively (p = 0.019). The median level of FGF23 showed a significant decrease only in the CaCO3 group. An increase in eGFR and a slightly decrease in urine phosphate were observed in the CaCO3 group; however, the data was found to be statistically not significant. No significant changes were noted in the serum calcium levels in both groups. Conclusion: The administration of calcium carbonate has been shown to be effective and safe for moderate CKD patients with normophosphatemia due to its effect in lowering FGF23 levels without escalating the serum calcium level.

Effects of calcifediol supplementation on markers of chronic kidney disease-mineral and bone disorder in dogs with chronic kidney disease.

BackgroundChronic kidney disease‐mineral and bone disorder (CKD‐MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor‐23 (FGF‐23) concentrations. Best practice for vitamin D metabolite supplementation in CKD‐MBD remains unknown.ObjectiveTo provide an extended‐release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD‐MBD.AnimalsTen dogs with International Renal Interest Society stages 2 and 3 CKD.MethodsIn a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), creatinine, calcium, phosphorus, PTH, plasma FGF‐23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined.ResultsAll serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7‐469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3‐66.0 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 56.9‐88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 81.4 ng/mL; range, 22.1‐151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9‐40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF‐23 concentrations increased by day 84 (median 1219 pg/mL; range, 229‐8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103‐4.145 pg/mL) (P < .01).Conclusions and Clinical ImportanceCalcifediol supplementation for 84 days was well‐tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long‐term supplementation would affect CKD progression and QOL.

Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.

To quantify Na18F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na18F-PET/CT uptake parameters in HB and FD. Relating Na18F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). In a prospective cohort study (n = 20), Na18F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R2 = 0.571, p = 0.004) and procollagen type 1N-terminal propeptide (R2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R2 = 0.596, p = 0.007 and R2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R2 = 0.518, p = 0.024), higher TLF (R2 = 0.478, p = 0.036), and higher levels of FGF-23 (R2 = 0.567, p = 0.034). Individualized Na18F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na18F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na18F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na18F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD.

Magnesium prevents vascular calcification in Klotho deficiency

Klotho knock-out mice are an important model for vascular calcification, which is associated with chronic kidney disease. In chronic kidney disease, serum magnesium inversely correlates with vascular calcification. Here we determine the effects of serum magnesium on aortic calcification in Klotho knock-out mice treated with a minimal or a high magnesium diet from birth. After eight weeks, serum biochemistry and aorta and bone tissues were studied. Protective effects of magnesium were characterized by RNA-sequencing of the aorta and micro-CT analysis was performed to study bone integrity. A high magnesium diet prevented vascular calcification and aortic gene expression of Runx2 and matrix Gla protein found in such mice on the minimal magnesium diet. Differential expression of inflammation and extracellular matrix remodeling genes accompanied the beneficial effects of magnesium on calcification. High dietary magnesium did not affect serum parathyroid hormone, 1,25-dihydroxyvitamin D3 or calcium. High magnesium intake prevented vascular calcification despite increased fibroblast growth factor-23 and phosphate concentration in the knock-out mice. Compared to mice on the minimal magnesium diet, the high magnesium diet reduced femoral bone mineral density by 20% and caused excessive osteoid formation indicating osteomalacia. Osteoclast activity was unaffected by the high magnesium diet. In Saos-2 osteoblasts, magnesium supplementation reduced mineralization independent of osteoblast function. Thus, high dietary magnesium prevents calcification in Klotho knock-out mice. These effects are potentially mediated by reduction of inflammatory and extracellular matrix remodeling pathways within the aorta. Hence magnesium treatment may be promising to prevent vascular calcification, but the risk for osteomalacia should be considered.

Effect of Paricalcitol on FGF-23 and Klotho in Kidney Transplant Recipients.

Paricalcitol decreases intact parathyroid hormone and the frequency of secondary hyperparathyroidism after kidney transplantation. This proof-of-concept study aimed to assess the effect of paricalcitol on fibroblast growth factor-23/KLOTHO axis in renal transplants. Twenty-nine subjects with secondary hyperparathyroidism received oral paricalcitol 1 μg/d for 3 months, and 8 patients matched by age, sex, and creatinine clearance, but with intact parathyroid hormone less than 100 pg/mL, were included as controls. Intact parathyroid hormone decreased in paricalcitol-treated patients (P < 0.0001). Serum fibroblast growth factor-23 enhanced (P < 0.01), whereas KLOTHO concentrations showed a trend to increase (P = 0.067). KLOTHO gene expression in peripheral blood mononuclear cells increased by 45.7% in paricalcitol-treated patients (P < 0.01), without change in controls. Paricalcitol administration resulted in a median percent decrease of 56% in methylated DNA levels of KLOTHO promoter (P < 0.001). The ratio of the unmethylated/methylated KLOTHO promoter DNA did not change in controls, but it increased by 177% in paricalcitol-treated subjects (P < 0.0001). The increase in this ratio was independently associated with the change in serum KLOTHO (r = 0.55, P < 0.01) and messenger RNA expression levels (r = 0.40, P < 0.05). Paricalcitol administration to renal transplant patients significantly reduced intact parathyroid hormone and increased fibroblast growth factor-23, with a trend to increase in serum KLOTHO. Paricalcitol-treated patients showed a decrease in the methylation of the KLOTHO promoter with an increment in the ratio of un-methyated/methylated DNA, which was associated with an increase of KLOTHO gene expression levels and serum KLOTHO concentrations. Long-term studies are needed to assess whether paricalcitol-induced increase in KLOTHO gene expression and serum concentrations may translate into beneficial clinical effects.

High serum soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease

This study aims to determine fibroblast growth factor-23 and soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease. A total of 76 patients with autosomal dominant polycystic kidney...

Increased Fibroblast Growth Factor-23 (FGF23) Does Not Alter Fetal-Placental Phosphorus Homeostasis or Prenatal Bone Formation and Mineralization

Increased Fibroblast Growth Factor-23 (FGF23) Does Not Alter Fetal-Placental Phosphorus Homeostasis or Prenatal Bone Formation and Mineralization

Bone Density Is Directly Associated With Glomerular Filtration and Metabolic Acidosis but Do Not Predict Fragility Fractures in Men With Moderate Chronic Kidney Disease

Hyperparathyroidism, vitamin D deficiency, increased fibroblast growth factor-23 (FGF-23), and metabolic acidosis promote bone fragility in chronic kidney disease (CKD). Although useful in predicting fracture risk in the general population, the role of dual-energy X-ray absorptiometry (DXA) in CKD remains uncertain. This cross-sectional study included 51 men aged 50–75 yr with moderate CKD. The stage 4 CKD patients had higher levels of parathyroid hormone (p < 0.001), FGF-23 (p = 0.029), and lowest 25-hydroxyvitamin D (p = 0.016), bicarbonate (p < 0.001), total femur (p = 0.003), and femoral neck (p = 0.011) T-scores compared with stage 3 CKD patients. Total femur and femoral neck T-scores were directly correlated with serum bicarbonate (p = 0.003, r = 0.447 and p = 0.005, r = 0.427, respectively) and estimated glomerular filtration rate (p = 0.024, r = 0.325 and p = 0.003, r = 0.313, respectively) but were not significantly associated with parathyroid hormone, 25-hydroxyvitamin D, or FGF-23. Only 3.9% of the participants had osteoporosis on DXA scan, whereas 31.4% reported a low-impact fracture. Our data point to a pivotal role of metabolic acidosis for bone impairment and to the inadequacy of DXA to evaluate bone fragility in CKD patients.

Lanthanum carbonate for the control of hyperphosphatemia in chronic renal failure patients: a new oral powder formulation &amp;ndash; safety, efficacy, and patient adherence

Chronic kidney disease (CKD) is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P) and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients.

Osteocyte and DMP1

Dentin matrix protein (DMP1) is a non-collagenous bone matrix protein produced specifically by osteocytes. Because of its highly acidic nature, DMP1 can participate in bone matrix mineralization through Ca(2 + ) binding capacity. Inactivating mutations in DMP1 have recently been shown to cause autosomal recessive hypophosphatemic rickets (ARHR) . In a murine model of ARHR, DMP1-null mice had increased fibroblast growth factor23 (FGF23) expression in osteocytes, indicating that DMP1 participates in the systemic phosphate regulation by restraining osteocytic FGF23 production. In addition, the DMP1 promoter has been used frequently as an osteocyte-specific promoter. However, DMP1 is not expressed in all osteocytes. DMP1 expression is seen in osteoblastic-, osteoid-, young osteocytes of the superficial bone layer, but is reduced remarkably in old osteocytes distributed over the bone inside. This pattern of DMP1 expression may influence the interpretation of DMP1 function and the studies that use the DMP1 promoter.