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Key Points Specific microorganisms use metal-containing minerals as electron sinks for heterotrophy-based respiration and electron and/or energy sources for autotrophic growth. The microbial cell envelope is an electrical and physical barrier that can be overcome by pathways that consist of redox proteins (for example, c -type cytochromes) and structural proteins, which span the entire width of the microbial cell envelope and enable the exchange of electrons with extracellular minerals. Some microorganisms can extend their redox-active surface beyond the confines of the cell envelope by forming microbial nanowires, which transfer electrons to distal minerals. c -Type cytochromes, microbial nanowires and other cellular structures are, or are suggested to be, involved in intercellular electron transfer between the same or different species or even domains. Minerals that contain metal ions can also function as electrical conductors and batteries to facilitate electron exchange among different groups of microorganisms. Microorganisms with extracellular electron transfer capabilities have been harnessed for the bioremediation of environmental contaminants, the production of biofuels, the production of nanomaterials with novel properties and biomining of copper, gold and other metals. Microorganisms with electron transfer capabilities, such as metal-reducing microorganisms, use specialized systems to exchange electrons between minerals and cells. In this Review, Shi et al . summarize the underlying molecular mechanisms, such as cytochromes and nanowires, and biotechnological applications. Electrons can be transferred from microorganisms to multivalent metal ions that are associated with minerals and vice versa. As the microbial cell envelope is neither physically permeable to minerals nor electrically conductive, microorganisms have evolved strategies to exchange electrons with extracellular minerals. In this Review, we discuss the molecular mechanisms that underlie the ability of microorganisms to exchange electrons, such as c -type cytochromes and microbial nanowires, with extracellular minerals and with microorganisms of the same or different species. Microorganisms that have extracellular electron transfer capability can be used for biotechnological applications, including bioremediation, biomining and the production of biofuels and nanomaterials.

Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.

The aim of this study was to assess the causal relationships between mineral metabolism disorders, representative of trace elements, and key aging biomarkers: telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN). Utilizing bidirectional Mendelian randomization (MR) analysis in combination with the two-stage least squares (2SLS) method, we explored the causal relationships between mineral metabolism disorders and these aging indicators. Sensitivity analysis can be used to determine the reliability and robustness of the research results. The results confirmed that a positive causal relationship was observed between mineral metabolism disorders and TL (p < 0.05), while the causal relationship with mtDNA-CN was not significant (p > 0.05). Focusing on subgroup analyses of specific minerals, our findings indicated a distinct positive causal relationship between iron metabolism disorders and both TL and mtDNA-CN (p < 0.05). In contrast, disorders in magnesium and phosphorus metabolism did not exhibit significant causal effects on either aging biomarker (p > 0.05). Moreover, reverse MR analysis did not reveal any significant causal effects of TL and mtDNA-CN on mineral metabolism disorders (p > 0.05). The combination of 2SLS with MR analysis further reinforced the positive causal relationship between iron levels and both TL and mtDNA-CN (p < 0.05). Notably, the sensitivity analysis did not indicate significant pleiotropy or heterogeneity within these causal relationships (p > 0.05). These findings highlight the pivotal role of iron metabolism in cellular aging, particularly in regulating TL and sustaining mtDNA-CN, offering new insights into how mineral metabolism disorders influence aging biomarkers. Our research underscores the importance of trace element balance, especially regarding iron intake, in combating the aging process. This provides a potential strategy for slowing aging through the adjustment of trace element intake, laying the groundwork for future research into the relationship between trace elements and healthy aging.

ABSTRACT The coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3–5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3–5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD–mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3–5D. Lay Summary Patients with chronic kidney disease (CKD) are at increased risk of fractures, causing disability, impaired quality of life and increased risk of death. Osteoporosis is a common cause of fractures, and different medications have the potential to reduce fracture risk in osteoporosis. Several diagnostic criteria have been developed to identify patients at risk of fracture who would benefit from treatment. However, in CKD, the identification of patients with increased fracture risk is complicated by mineral metabolism disturbances due to reduced kidney function. Furthermore, patients with more advanced CKD are often excluded from clinical trials and treatment recommendations for fracture risk reduction. This review discusses diagnostic possibilities and treatment options to reduce fracture risk in patients with CKD, based on disease mechanisms, clinical experience, and clinical and experimental research. Although more research is needed, we conclude that many diagnostic and therapeutic approaches to osteoporosis can be applied in patients with CKD.

This study investigated the effects of replacement of inorganic trace minerals (ITMs) by organic trace minerals (OTMs) on tissue mineral retention and fecal excretion in “Zhen Ning” yellow feather broiler breeders. Six hundred hens (initial BW: 1.70 ± 0.07 kg) aged 40 weeks were randomly divided into five treatments, with four replicates of 30 broiler breeders each. Experimental treatments were as follows: (1) ITM (Cu, Zn, Fe, Mn, Se providing commercially recommended concentrations), (2) L-ITM (50% of the ITM, except for Se), (3) VL-OTM (37.5% of the ITM, except for Se), (4) L-OTM (equivalent to L-ITM), and (5) OTM (62.5% of the ITM, except for Se). The duration of the study was 10 weeks including 2 weeks for adaptation. Compared with the L-ITM treatment, high-level supplementation of minerals in ITM and OTM increased the concentration of serum Mn and Se, pectoral Fe and pancreas Cu, and Fe ( P  < 0.05). Birds fed with OTM dietary exhibited comparable mineral retention in muscle compared with ITM. Differences were observed between L-ITM and L-OTM in serum Mn and Se, pectoral Fe, Zn, and Se, and heart Se with L-OTM retaining higher mineral concentrations than L-ITM ( P  < 0.05). L-OTM retained identical concentration with ITM treatment, except for the pancreatic Fe. All three organic diets reduced the Zn in excreta compared with the two inorganic diets ( P  < 0.05). This study indicates that replacement of dietary ITMs by OTMs improved mineral deposition in tissues and reduced fecal mineral excretion in broiler breeders under the conditions of this study.

The authoritative reference to bone diseases and disorders of mineral metabolism, revised and updated Now in its ninth edition, The Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism offers an updated and comprehensive guide to bone and mineral health. Since it was first published 30 years ago, the Primer has become the leading reference on the topic. With contributions from noted experts, the text explores basic biological factors of healthy development and disease states and makes the information accessible for clinical interventions. The ninth edition provides concise coverage of the widest possible spectrum of metabolic bone diseases and disorders of mineral metabolism. The new edition of this invaluable reference expands coverage and includes the most recent developments in the field that help to strengthen its usefulness and ensure that the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism maintains its place as the pre-eminent reference on bone and mineral health. This vital resource:  * Provides the most accurate, up-to-date evidence-based information on basic and clinical bone science * Includes more than 10 new chapters and contributions from 300 authors from wide-ranging international research centers * Captures the very cutting edge of research covering mineral homeostasis, osteoporosis and other metabolic bone diseases, skeletal measurement technologies, and genetics * Presents a new companion website with useful supplementary materials at www.asbmrprimer.com Written for advanced students, clinicians, and researchers working in the field of bone health and disease, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism is the definitive, one-stop reference for anyone working in the field of bone health and disease.

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

Fermented milk products like yogurt or soft cheese provide calcium, phosphorus, and protein. All these nutrients influence bone growth and bone loss. In addition, fermented milk products may contain prebiotics like inulin which may be added to yogurt, and provide probiotics which are capable of modifying intestinal calcium absorption and/or bone metabolism. On the other hand, yogurt consumption may ensure a more regular ingestion of milk products and higher compliance, because of various flavors and sweetness. Bone mass accrual, bone homeostasis, and attenuation of sex hormone deficiency-induced bone loss seem to benefit from calcium, protein, pre-, or probiotics ingestion, which may modify gut microbiota composition and metabolism. Fermented milk products might also represent a marker of lifestyle promoting healthy bone health.

GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown. In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone. GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.

In this Review, the author discusses new insights into the pathogenesis of chronic kidney disease and describes a novel mechanism of ageing, both in the context of the fibroblast growth factor (FGF)–Klotho endocrine axis. In addition, the author proposes a new paradigm for dietary phosphate restriction in which phosphate restriction is started when serum FGF-23 level starts to rise, regardless of serum phosphate level. High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that can induce various cellular responses, including the osteogenic transformation of vascular smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial cells. Calciprotein particles are detected in the serum of animal models of kidney disease and in patients with chronic kidney disease (CKD) and might be associated with a (mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos that regulate phosphate homeostasis and ageing. These observations raise the possibility that calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is expected to provide novel diagnostic markers and therapeutic targets in CKD. Key Points Calciprotein particles are cytotoxic nanoparticles composed of inorganic calcium–phosphate crystals and mineral binding proteins, such as fetuin-A Calciprotein particles circulate in the blood of patients with chronic kidney disease (CKD) and may contribute to vascular calcification, chronic inflammation and a premature-ageing phenotype Raised phosphate intake and/or decreased nephron number increase the rate of phosphate excretion per nephron, potentially causing calciprotein particle formation in the tubular lumen and tubular injury Serum fibroblast growth factor 23 (FGF-23) level correlates with phosphate excretion per nephron and, when combined with 24 h urinary phosphate excretion, may be useful for estimating changes in residual nephron number A new paradigm for phosphate restriction proposed in this Review argues for phosphate binders to be used in patients with CKD and an abnormally high FGF-23 level, regardless of serum phosphate level The therapeutic goal is to reduce serum FGF-23 level but not serum phosphate level, with the primary aim of preventing histological kidney damage and progression of CKD without increasing vascular calcification and cardiovascular events