Search Results (69)

Background: The increasing prevalence of processed foods has significantly elevated dietary phosphorus intake globally, posing a risk to skeletal health. Elevated serum phosphate promotes parathyroid hormone (PTH) release, leading to bone resorption and decreased bone formation. Objective: This study investigated the influence of chronically elevated phosphorus intake on bone structure in rats with normal renal function, focusing on the Receptor Activator of Nuclear factor Kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway and its related components, leucine rich repeat containing G protein-coupled receptor 4 (LGR4), and R-spondins (RSPOs). Methods: Rats were fed a high-phosphorus diet, followed by assessment of the bone microstructure and of the expression of key signalling molecules. Results: Elevated phosphorus intake induced significant bone deterioration, particularly in the trabecular bone compartment, associated with alterations in the RANK/RANKL/OPG pathway and in the LGR4 and RSPO1 and RSPO4 signalling components in bone. Moreover, we also observed changes in RANKL, RSPO1 and RSPO4 serum levels in the rats that had received a high-phosphorus diet. Conclusions: These findings highlight the detrimental impact of excessive dietary phosphorus on skeletal health, even without renal impairment, and suggest that components of this pathway, particularly RSPO1 and RSPO4, could serve as potential biomarkers of bone deterioration. The widespread consumption of phosphorus-rich processed foods underscores the importance of nutritional education to mitigate these skeletal risks in industrialized populations. Full article

Phosphorus is one of the most abundant minerals in the body and plays a critical role in numerous cellular and metabolic processes. Most of the phosphate is deposited in bones, 14% is present in soft tissues as various organic phosphates, and only 1% is found in extracellular space, mainly as inorganic phosphate. The plasma inorganic phosphate concentration is closely maintained between 2.5 and 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and vitamin D, which tightly regulate the phosphate trafficking across the gastrointestinal tract, kidneys, and bones. Disruption of the strict hemostatic control of phosphate balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) among populations. Individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphate metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. In early stages of CKD, adaptive processes involving FGF-23, PTH, and vitamin D occur in response to dietary phosphate load to maintain plasma phosphate level in the normal range. However, as the CKD progresses, these adaptive events are unable to overcome phosphate retention from continued dietary phosphate intake and overt hyperphosphatemia ensues. As these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF, it appears logical to strictly control serum phosphate. Conventional dialysis is inadequate in removing phosphate and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition. Phosphate binders help to reduce phosphate levels but come with a sizable pill burden and high financial costs and are associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum, or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given the aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium–hydrogen exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is a lack of convincing clinical data to demonstrate improvement in outcomes in KF with the lowering of phosphorus level. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus-sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF. Full article

Parathyroid hormone-related protein (PTHrP) and retinol-binding protein 4 (RBP4) have been associated with a worse prognosis of kidney disease. Recently, the direct interconnection between PTHrP and the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor whose activation is nephroprotective, has been discovered. The aim of this study was to analyze the relationship between PTHrP, PPARγ, and RBP4. For this purpose, we analyzed the levels of these proteins, which were studied in the kidneys of five experimental groups of mice at 6 weeks of age: controls, diabetics, insulin-treated diabetics, transgenic mice overexpressing PTHrP at the renal level, and the latter mice that were also induced with diabetes. In addition, we also analyzed the expression levels of these molecules in two mouse podocyte cell lines, controls and PPARγKO, subjected to a lipotoxic insult by palmitic acid. We found that RBP4 and PTHrP are increased in the kidney in pathological conditions and that insulin and PPARγ act regulating PTHrP and RBP4 expression, suggesting that the regulation of this system is critical for the maintenance of renal homeostasis and how it becomes imbalanced in different pathophysiological conditions. Full article

Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2⁺ osteoprogenitors become Runx2⁺Sp7⁺ preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development. Full article

The most widely used synthetic glucocorticoid, dexamethasone (DEX), causes stunted growth in children when used excessively or for long periods of time; however, there are still plenty of pediatric patients require long-term treatment with DEX. As an alternative, growth hormone is used in combination, but it has side effects, a high cost, and psychological factors, and it is not satisfactory in terms of effectiveness. It is necessary to develop a safe and affordable treatment that can replace it. The Korean Food and Drug Administration approved HT042, a standardized functional food ingredient, with the claim that it can help height growth of children. In this study, it was found that HT042 activated the Indian hedgehog/parathyroid hormone-related protein signaling pathway and enhanced the number of growth hormone receptors and insulin-like growth factor-1 receptors on the growth plate surface, which were reduced by DEX treatment, and restored growth retardation. In metatarsal bone and primary chondrocyte models, it was found that HT042 can promote the length of growth plate and recover DEX-induced growth retardation. It was also found that HT042 promotes cell proliferation using bromodeoxyuridine and terminal deoxynucleotidyl transferase dUTP nick end labeling assays; moreover, we verified increased expression of GHR/IGF-1R and Ihh/PTHrP pathway activity using qRT-PCR, western blotting, and siRNA analyses to verify its direct action on the growth plate. The anti-apoptotic effect of HT042 was identified by regulating the expression of apoptotic factors such as caspase-3, Bcl2, Bclx, and Bax. These results were identified using both ex vivo and in vitro models. Our study verified that co-administration of HT042 could recover the DEX induced growth retardation Full article

Chronic kidney disease (CKD) causes specific hormonal disturbances, such as variations in leptin and testosterone levels and function. These disturbances can promote errors in signaling interaction and cellular information processing and can be implicated in the pathogenesis of atherosclerosis. This study investigates the factors that affect leptin in CKD patients and examines how leptin is related to markers of vascular disease. We conducted a cross-sectional study of 162 patients with CKD in pre-dialysis and dialysis stages. We recorded clinical and laboratory data, including leptin, testosterone, and subclinical atherosclerosis markers like brachial–ankle pulse wave velocity (ba PWV) in pre-dialysis CKD patients and flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) in hemodialysis (HD) patients. Leptin was significantly correlated with testosterone in CKD pre-dialysis stages (p < 0.001) and also in HD (p = 0.026), with adipose tissue mass in pre-dialysis stages (p < 0.001), and also in HD (p < 0.001). In women HD patients, leptin correlated with NMD (p = 0.039; r = −0.379); in all HD patients, leptin correlated with C reactive protein (p = 0.007; r = 0.28) and parathormone (p = 0.039; r = −0.220). Our research emphasizes the connection between leptin, adipose tissue, and testosterone in all stages of CKD. Leptin was associated with NMD in HD women and correlated with inflammatory syndrome and parathyroid hormone in all HD patients. Full article

The aim of this study was to evaluate changes in the concentration of N-terminal type I collagen extension pro-peptide (PINP), tartrate-resistant acid phosphatase (TRAcP), and parathyroid hormone-related protein (PTHrP) in saliva during orthodontic treatment in order to evaluate whether changes in bone turnover marker (BTM) concentration can help highlight the effects of orthodontic mechanical loading in the absence of clinical evidence of tooth movement in terms of tooth movement. Saliva samples from 25 apparently healthy young subjects (10 females and 15 males) were collected using Salivette^® (Sarstedt) with cotton swabs and the concentrations of PTHrP, TRAcP 5b, and PINP were analyzed at time 0 (T1), 25 days (T2), and at 45 days (T3). Differences in the median value of biomarker levels between baseline T1 and follow-up of the different groups (T2 and T3) were assessed using the non-parametric Mann–Whitney U test. Trough concentrations of P1NP, PTHrP, and TRAcP were 0.80 µg/L, 0.21 ng/mL, and 0.90 U/L above the method LOD. The non-parametric Mann–Whitney U test confirmed a statistically significant difference in T1 versus concentrations of T2 and T3. All subjects evaluated had a statistically significant difference between T1 vs. T3. when compared with the specific critical difference (RCV) for the analyte The results obtained demonstrate that the evaluation of BTM changes in saliva can help the evaluation of orthodontic procedures and the monitoring of biomechanical therapy. Full article

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate–calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases. Full article

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research. Full article

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1β maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107–111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5′-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1β and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis. Full article

Background: During the early stages of human fetal development, the fetal skeleton system is chiefly made up of cartilage, which is gradually replaced by bone. Fetal bone development is mainly regulated by the parathyroid hormone parathormone (PTH) and PTH-related protein, with specific calprotectin playing a substantial role in cell adhesion and chemotaxis while exhibiting antimicrobial activity during the inflammatory osteogenesis process. The aim of our study was to measure the levels of PTH and calprotectin in early second trimester amniotic fluid and to carry out a comparison between the levels observed among normal full-term pregnancies (control group) and those of the groups of embryos exhibiting impaired or enhanced growth. Methods: For the present prospective study, we collected amniotic fluid samples from pregnancies that underwent amniocentesis at 15 to 22 weeks of gestational age during the period 2021–2023. Subsequently, we followed up on all pregnancies closely until delivery. Having recorded fetal birthweights, we then divided the neonates into three groups: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Results: In total, 64 pregnancies, including 14 SGA, 10 LGA, and 40 AGA fetuses, were included in our study. Both substances were detected in early second trimester amniotic fluid in both groups. Concentrations of calprotectin differed significantly among the three groups (p = 0.033). AGA fetuses had a lower mean value of 4.195 (2.415–6.425) IU/mL, whereas LGA fetuses had a higher mean value of 6.055 (4.887–13.950) IU/mL, while SGA fetuses had a mean value of 5.475 (3.400–9.177) IU/mL. Further analysis revealed that only LGA fetuses had significantly higher calprotectin concentrations compared to AGA fetuses (p = 0.018). PTH concentration was similar between the groups, with LGA fetuses having a mean value of 13.18 (9.51–15.52) IU/mL, while SGA fetuses had a mean value of 14.18 (9.02–16.00) IU/mL, and AGA fetuses had similar concentrations of 13.35 (9.05–15.81) IU/mL. The differences in PTH concentration among the three groups were not statistically significant (p = 0.513). Conclusions: Calprotectin values in the amniotic fluid in the early second trimester were higher in LGA fetuses compared to those in the SGA and AGA categories. LGA fetuses can possibly be in a state of low-grade chronic inflammation due to excessive fat deposition, causing oxidative stress in LGA fetuses and, eventually, the release of calprotectin. Moreover, PTH concentrations in the amniotic fluid of early second trimester pregnancies were not found to be statistically correlated with fetal growth abnormalities in either LGA or SGA fetuses. However, the early time of collection and the small number of patients in our study should be taken into account. Full article

(1) Background: Uremic pruritus (UP) is a common and taxing symptom in patients on maintenance hemodialysis (MHD). We have previously shown that blood lead levels (BLLs) and blood aluminum levels (BALs) were separately positively associated with UP in MHD patients. We also found that blood cadmium levels (BCLs) were positively associated with all-cause mortality and cardiovascular-related mortality in MHD patients. We wondered whether there is any correlation between BCLs and UP after adjusting for BLLs and BALs. (2) Methods: Patients enrolled in this study were all from three hemodialysis (HD) centers at Chang Gung Memorial Hospital, Lin-Kou Medical Center, including both the Taipei and Taoyuan branches. Correlations between UP and BLLs, BALs, BCLs, and other clinical data were analyzed. (3) Results: Eight hundred and fifty-three patients were recruited. Univariate logistic regressions showed that diabetes mellitus, hepatitis B virus infection, hepatitis C virus infection, HD duration, hemodiafiltration, dialysis clearance of urea, normalized protein catabolic rate, non-anuria, serum albumin levels, log (intact-parathyroid hormone levels), total serum cholesterol levels, serum low-density lipoprotein levels, log (blood aluminum levels), and log (blood lead levels) were associated with UP. Although log BCLs were not significantly associated with UP (p = 0.136) in univariate analysis, we still included log BCLs in multivariate logistic regression to verify their effect on UP given that our aim in this study was to verify associations between serum heavy metals and UP. Multivariate logistic regressions showed that log BLLs (OR: 27.556, 95% CI: 10.912–69.587, p < 0.001) and log BALs (OR: 5.485, 95% CI: 2.985–10.079, p < 0.001) were positively associated with UP. The other logistic regression, which stratified BLLs and BALs into high and low BLLs and BALs, respectively, showed that high BLLs or high BALs (low BLLs and low BALs as reference) (OR: 3.760, 95% CI: 2.554–5.535, p < 0.001) and high BLLs and high BALs combined (low BLLs and low BALs as reference) (OR: 10.838, 95% CI: 5.381–21.828, p < 0.001) were positively correlated with UP. (4) Conclusions: BLLs and BALs were positively correlated with UP. BCLs were not correlated with UP. Clinicians should pay more attention to the environmental sources of lead and aluminum to prevent UP. Full article

Bone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, Alpl) enzyme activity. The abnormal development of the cranial base growth plates (synchondroses) and abnormal skull shapes have also been demonstrated in global Alpl^−/− mice. To distinguish local vs. systemic effects of TNAP on skull development, we utilized P0-Cre to knockout Alpl only in cranial neural crest-derived tissues using Alpl flox mice. Here, we show that Alpl deficiency using P0-Cre in cranial neural crest leads to skull shape defects and the deficient growth of the intersphenoid synchondrosis (ISS). ISS chondrocyte abnormalities included increased proliferation in resting and proliferative zones with decreased apoptosis in hypertrophic zones. ColX expression was increased, which is indicative of premature differentiation in the absence of Alpl. Sox9 expression was increased in both the resting and prehypertrophic zones of mutant mice. The expression of Parathyroid hormone related protein (PTHrP) and Indian hedgehog homolog (IHH) were also increased. Finally, cranial base organ culture revealed that inorganic phosphate (P_i) and pyrophosphate (PP_i) have specific effects on cell signaling and phenotype changes in the ISS. Together, these results demonstrate that the TNAP expression downstream of Alpl in growth plate chondrocytes is essential for normal development, and that the mechanism likely involves Sox9, PTHrP, IHH and PP_i. Full article

Parathyroid-hormone-related protein (PTHrP) is encoded by the PTHLH gene which, via alternative promoter usage and splicing mechanisms, can give rise to at least three isoforms of 139, 141, and 173 amino acids with distinct C-terminals. PTHrP is subjected to different post-translational processing that generates smaller bioactive forms, comprising amino terminus, mid-region (containing a nuclear/nucleolar targeting signal), and carboxy terminus peptides. Both the full-length protein and the discrete peptides are key controllers of viability, proliferation, differentiation, and apoptosis in diverse normal and pathological biological systems via the reprogramming of gene expression and remodulation of PKA or PKC-mediated signalization mechanisms. The aim of this review is to pick up selected studies on PTHrP-associated signatures as revealed by molecular profiling assays, focusing on the available data about exemplary differentiating, differentiated, or nontumoral cell and tissue models. In particular, the data presented relate to adipose, bone, dental, cartilaginous, and skin tissues, as well as intestinal, renal, hepatic, pulmonary, and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis-, and diabetes-related changes as diseased states. When reported, the biochemical and/or physiological aspects associated with the specific molecular modulation of gene expression and signal transduction pathways in the target model systems under examination are also briefly described. Full article

Strontium (Sr) belongs to the same group in the periodic table as calcium (Ca). Sr level can serve as an index of rumen Ca absorption capacity; however, the effects of Sr on Ca²⁺ metabolism are unclear. This study aims to investigate the effect of Sr on Ca²⁺ metabolism in bovine rumen epithelial cells. The bovine rumen epithelial cells were isolated from the rumen of newborn Holstein male calves (n = 3, 1 day old, 38.0 ± 2.8 kg, fasting). The half maximal inhibitory concentration (IC50) of Sr-treated bovine rumen epithelial cells and cell cycle were used to establish the Sr treatment model. Transcriptomics, proteomics, and network pharmacology were conducted to investigate the core targets of Sr-mediated regulation of Ca²⁺ metabolism in bovine rumen epithelial cells. The data of transcriptomics and proteomics were analyzed using bioinformatic analysis (Gene Ontology and Kyoto Encyclopedia of genes/protein). Quantitative data were analyzed using one-way ANOVA in GraphPad Prism 8.4.3 and the Shapiro–Wilk test was used for the normality test. Results presented that the IC50 of Sr treatment bovine rumen epithelial cells for 24 h was 43.21 mmol/L, and Sr increased intracellular Ca²⁺ levels. Multi-omics results demonstrated the differential expression of 770 mRNAs and 2436 proteins after Sr treatment; network pharmacology and reverse transcriptase polymerase chain reaction (RT-PCR) revealed Adenosylhomocysteine hydrolase-like protein 2 (AHCYL2), Semaphoring 3A (SEMA3A), Parathyroid hormone-related protein (PTHLH), Transforming growth factor β2 (TGF-β2), and Cholesterol side-chain cleavage enzyme (CYP11A1) as potential targets for Sr-mediated Ca²⁺ metabolism regulation. Together these results will improve the current comprehension of the regulatory effect of Sr on Ca²⁺ metabolism and pave a theoretical basis for Sr application in bovine hypocalcemia. Full article