Role of phosphate sensing in bone and mineral metabolism.
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ABSTRACT:
SUBMITTER: Chande S
PROVIDER: S-EPMC8607960 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.
| S-EPMC2586800 | biostudies-literature
Project description:The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphoglycoprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles pathway (MVP). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.
| S-EPMC4470732 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is a risk factor for osteoporosis. The effects of T2DM and anti-diabetic agents on bone and mineral metabolism have been observed. Sodium-glucose co-transporter 2 inhibitors (SGLT-2is) promote urinary glucose excretion, reduce blood glucose level, and improve the cardiovascular and diabetic nephropathy outcomes. In this review, we focused on the extraglycemic effect and physiological regulation of SGLT-2is on bone and mineral metabolism. SGLT-2is affect the bone turnover, microarchitecture, and bone strength indirectly. Clinical evidence of a meta-analysis showed that SGLT-2is might not increase the risk of bone fracture. The effect of SGLT-2is on bone fracture is controversial, and further investigation from a real-world study is needed. Based on its significant benefit on cardiovascular and chronic kidney disease (CKD) outcomes, SGLT-2is are an outstanding choice. Bone mineral density (BMD) and fracture risk evaluation should be considered for patients with a high risk of bone fracture.
| S-EPMC9302585 | biostudies-literature
Project description:Phosphorus-based food additives can substantially increase total phosphorus intake per day, but the effect of these additives on endocrine factors regulating bone and mineral metabolism is unclear.This study aimed to examine the effect of phosphorus additives on markers of bone and mineral metabolism. Design and Setting, and Participants: This was a feeding study of 10 healthy individuals fed a diet providing ?1000 mg of phosphorus/d using foods known to be free of phosphorus additives for 1 week (low-additive diet), immediately followed by a diet containing identical food items; however, the foods contained phosphorus additives (additive-enhanced diet). Parallel studies were conducted in animals fed low- (0.2%) and high- (1.8%) phosphorus diets for 5 or 15 weeks.The changes in markers of mineral metabolism after each diet period were measured.Participants were 32 ± 8 years old, 30% male, and 70% black. The measured phosphorus content of the additive-enhanced diet was 606 ± 125 mg higher than the low-additive diet (P < .001). After 1 week of the low-additive diet, consuming the additive-enhanced diet for 1 week significantly increased circulating fibroblast growth factor 23 (FGF23), osteopontin, and osteocalcin concentrations by 23, 10, and 11%, respectively, and decreased mean sclerostin concentrations (P < .05 for all). Similarly, high-phosphorus diets in mice significantly increased blood FGF23, osteopontin and osteocalcin, lowered sclerostin, and decreased bone mineral density (P < .05 for all).The enhanced phosphorus content of processed foods can disturb bone and mineral metabolism in humans. The results of the animal studies suggest that this may compromise bone health.
| S-EPMC4702463 | biostudies-literature
Project description:Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors.
| S-EPMC5026566 | biostudies-literature
Project description:A subset of PHPT patients exhibit a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other dysfunctions, but the underlying reasons for this disparity in clinical presentation remain unknown.We sought to identify new mechanistic indices that could inform more personalized management of PHPT.Pre-, peri-, and postoperative data and demographic, clinical, and pathological information from patients undergoing parathyroidectomy for PHPT were collected. Univariate and partial Spearman correlation was used to estimate the association of parathyroid tumor calcium sensing capacity with select variables.An unselected series of 237 patients aged >18years and undergoing parathyroidectomy for PHPT were enrolled.Calcium sensing capacity, expressed as the concentration required for half-maximal biochemical response (EC50), was evaluated in parathyroid tumors from an unselected series of 74 patients and assessed for association with clinical parameters. The hypothesis was that greater disease severity would be associated with attenuated calcium sensitivity and biochemically autonomous parathyroid tumor behavior.Parathyroid tumors segregated into two distinct groups of calcium responsiveness (EC50<3.0 and ?3.0mM). The low EC50 group (n=27) demonstrated a mean calcium EC50 value of 2.49mM [95% confidence interval (CI): 2.43-2.54mM], consistent with reference normal activity. In contrast, the high EC50 group (n=47) displayed attenuated calcium sensitivity with a mean EC50 value of 3.48mM [95% CI: 3.41-3.55mM]. Retrospective analysis of the clinical registry data suggested that high calcium EC50 patients presented with a more significant preoperative bone mineral density (BMD) deficit with a t-score of -2.7, (95% CI: -3.4 to -1.9) versus 0.9, (95% CI: -2.1 to -0.4) in low EC50 patients (p<0.001). After adjusting for gender, age, BMI, 25 OH vitamin D level and preoperative iPTH, lowest t-score and calcium EC50 were inversely correlated, with a partial Spearman correlation coefficient of -0.35 (p=0.02).Impaired calcium sensing in parathyroid tumors is selectively observed in a subset of patients with more severe bone mineral density deficit. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity as measured by bone mineral density in patients with PHPT.
| S-EPMC5561769 | biostudies-literature
Project description:BackgroundChronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic syndrome characterized by imbalances in mineral homeostasis, renal osteodystrophy (ROD) and ectopic calcification. The mechanisms underlying this syndrome in individuals with chronic kidney disease (CKD) are not yet clear.MethodsWe examined the effect of normal phosphate (NP) or high phosphate (HP) feeding in the setting of CKD on bone pathology, serum biochemistry and vascular calcification in calcification-prone dilute brown non-agouti (DBA/2) mice.ResultsIn both NP and HP-fed CKD mice, elevated serum parathyroid hormone and alkaline phosphatase (ALP) levels were observed, but serum phosphorus levels were equivalent compared with sham controls. CKD mice on NP diet showed trabecular alterations in the long bone consistent with high-turnover ROD, including increased trabecular number with abundant osteoblasts and osteoclasts. Despite trabecular bone and serum biochemical changes, CKD/NP mice did not develop vascular calcification. In contrast, CKD/HP mice developed arterial medial calcification (AMC), more severe trabecular bone alterations and cortical bone abnormalities that included decreased cortical thickness and density, and increased cortical porosity. Cortical bone porosity and trabecular number strongly correlated with the degree of aortic calcification.ConclusionsHP feeding was required to induce the full spectrum of CKD-MBD symptoms in CKD mice.
| S-EPMC3539425 | biostudies-literature
Project description:OBJECTIVES:Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. METHODS:This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (?-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. RESULTS:The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with ?-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. CONCLUSION:Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.
| S-EPMC7061317 | biostudies-literature
Project description:BackgroundDiabetic patients on haemodialysis have a higher risk of mortality than non-diabetic patients. The aim of this COSMOS (Current management of secondary hyperparathyroidism: a multicentre observational study) analysis was to assess whether bone and mineral laboratory values [calcium, phosphorus and parathyroid hormone (PTH)] contribute to this risk.MethodsCOSMOS is a multicentre, open-cohort, 3-year prospective study, which includes 6797 patients from 227 randomly selected dialysis centres in 20 European countries. The association between mortality and calcium, phosphate or PTH was assessed using Cox proportional hazard regression models using both penalized splines smoothing and categorization according to KDIGO guidelines. The effect modification of the association between the relative risk of mortality and serum calcium, phosphate or PTH by diabetes was assessed.ResultsThere was a statistically significant effect modification of the association between the relative risk of mortality and serum PTH by diabetes (P = .011). The slope of the curve of the association between increasing values of PTH and relative risk of mortality was steeper for diabetic compared with non-diabetic patients, mainly for high levels of PTH. In addition, high serum PTH (>9 times the normal values) was significantly associated with a higher relative risk of mortality in diabetic patients but not in non-diabetic patients [1.53 (95% confidence interval 1.07-2.19) and 1.17 (95% confidence interval 0.91-1.52)]. No significant effect modification of the association between the relative risk of mortality and serum calcium or phosphate by diabetes was found (P = .2 and P = .059, respectively).ConclusionThe results show a different association of PTH with the relative risk of mortality in diabetic and non-diabetic patients. These findings could have relevant implications for the diagnosis and treatment of chronic kidney disease-mineral and bone disorders.
| S-EPMC10615625 | biostudies-literature
Project description:Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P = 0.003), femoral neck (P = 0.006) and total hip (P = 0.005), and was inversely associated with intact parathyroid hormone (PTH) (P = 8.18E-09) and procollagen type 1 N-terminal propeptide (P1NP) (P = 0.020). By contract, the associations of bioavailable and free 25OHD with all tested outcomes were negligible (all P > 0.05). The use of four single nucleotide polymorphisms, GC-rs2282679, NADSYN1-rs12785878, CYP2R1-rs10741657 and CYP24A1-rs6013897, as candidate instrumental variables in MR analyses showed that none of the two stage least squares models provided evidence for associations between serum 25OHD and either BMD or bone metabolism markers (all P > 0.05). We suggest that after controlling for unidentified confounding factors in MR analyses, the associations between genetically low serum 25OHD and BMD and bone metabolism markers are unlikely to be causal.
| S-EPMC5021966 | biostudies-literature