Abstract
BackgroundCalcium deficiency is a global public-health problem. Although the initial stage of calcium deficiency can lead to metabolic alterations or potential pathological changes, calcium deficiency is difficult to diagnose accurately. Moreover, the details of the molecular mechanism of calcium deficiency remain somewhat elusive. To accurately assess and provide appropriate nutritional intervention, we carried out a global analysis of metabolic alterations in response to calcium deficiency.MethodsThe metabolic alterations associated with calcium deficiency were first investigated in a rat model, using urinary metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis. Correlations between dietary calcium intake and the biomarkers identified from the rat model were further analyzed to confirm the potential application of these biomarkers in humans.ResultsUrinary metabolic-profiling analysis could preliminarily distinguish between calcium-deficient and non-deficient rats after a 2-week low-calcium diet. We established an integrated metabonomics strategy for identifying reliable biomarkers of calcium deficiency using a time-course analysis of discriminating metabolites in a low-calcium diet experiment, repeating the low-calcium diet experiment and performing a calcium-supplement experiment. In total, 27 biomarkers were identified, including glycine, oxoglutaric acid, pyrophosphoric acid, sebacic acid, pseudouridine, indoxyl sulfate, taurine, and phenylacetylglycine. The integrated urinary metabonomics analysis, which combined biomarkers with regular trends of change (types A, B, and C), could accurately assess calcium-deficient rats at different stages and clarify the dynamic pathophysiological changes and molecular mechanism of calcium deficiency in detail. Significant correlations between calcium intake and two biomarkers, pseudouridine (Pearson correlation, r = 0.53, P = 0.0001) and citrate (Pearson correlation, r = -0.43, P = 0.001), were further confirmed in 70 women.ConclusionsTo our knowledge, this is the first report of reliable biomarkers of calcium deficiency, which were identified using an integrated strategy. The identified biomarkers give new insights into the pathophysiological changes and molecular mechanisms of calcium deficiency. The correlations between calcium intake and two of the biomarkers provide a rationale or potential for further assessment and elucidation of the metabolic responses of calcium deficiency in humans.
Highlights
Calcium deficiency is a global public-health problem
Serum biochemical indicators and bone-mineral density There was a significant difference between the low-calcium group (LCG) and normal-calcium group (NCG) rats for mean serum PTH and 1,25(OH)2D3 at week 4, for serum alkaline phosphatase (AP), PTH, and 1,25(OH)2D3 at week 8, and for all of the serum indicators plus BMD at week 12 (Table 1)
Urinary metabolic-profiling analysis of experiment I All of the urine samples (n = 384) from weeks 1-12 collected in experiment I were analyzed by ultra-performance liquid chromatography (UPLC)/Q-TOF mass spectrometry (MS)/MS in electrospray ionization (ESI)
Summary
Calcium deficiency is a global public-health problem. the initial stage of calcium deficiency can lead to metabolic alterations or potential pathological changes, calcium deficiency is difficult to diagnose accurately. To accurately assess and provide appropriate nutritional intervention, we carried out a global analysis of metabolic alterations in response to calcium deficiency. A number of methods are currently used to assess calcium nutrition status, including epidemiological survey, calcium-balance study [12,13,14], serum biochemical analysis [15,16], and radiological examination [17]; none of these is suitable for large-scale screening of calcium deficiency in a population. Radiological examination, in general, cannot provide a diagnosis of calcium deficiency during the early stages, unless there is pathological injury to bone [17]. A sensitive and non-invasive tool is needed to assess calcium nutrition status accurately and to identify biomarkers that can elucidate the mechanisms underlying calcium deficiency
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