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Review
. 2019 Oct 25;11(11):2576.
doi: 10.3390/nu11112576.

Role of Citrate in Pathophysiology and Medical Management of Bone Diseases

Donatella Granchi  1 , Nicola Baldini  1   2 , Fabio Massimo Ulivieri  3 , Renata Caudarella  4
Affiliations
Review

Role of Citrate in Pathophysiology and Medical Management of Bone Diseases

Donatella Granchi et al. Nutrients. .

Abstract

Citrate is an intermediate in the "Tricarboxylic Acid Cycle" and is used by all aerobic organisms to produce usable chemical energy. It is a derivative of citric acid, a weak organic acid which can be introduced with diet since it naturally exists in a variety of fruits and vegetables, and can be consumed as a dietary supplement. The close association between this compound and bone was pointed out for the first time by Dickens in 1941, who showed that approximately 90% of the citrate bulk of the human body resides in mineralised tissues. Since then, the number of published articles has increased exponentially, and considerable progress in understanding how citrate is involved in bone metabolism has been made. This review summarises current knowledge regarding the role of citrate in the pathophysiology and medical management of bone disorders.

Keywords: bone metabolism; bone mineral density; bone remodelling; citrate supplement; kidney diseases; osteopenia; osteoporosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of the biomedical citations indexed by PubMed over seven decades (n = 949, from 1949 to 2018). The search query focused on “citrate” and “bone”, with a search restricted to the terms “Title”, “Abstract” or “Medical Subject Headings”. Only citations related to studies on humans are included with the exception of those dealing with citrate as an anticoagulant.
Figure 2
Figure 2
The four domains of citrate homeostasis. The plasma level of citrate mainly depends on four sources, i.e., nutritional intake, renal clearance, cellular metabolism, and bone remodelling. Food citrate is rapidly introduced into the circulation, filtered at the glomerular level, and eventually reabsorbed according to physiological needs. The citrate uptake from the extracellular milieu may occur only when specific transporter proteins are expressed, i.e., sodium-dicarboxylate (NaDC)1 belonging to the “solute carrier” 13 (Slc13) family. The citrate produced by mitochondria only marginally contributes to citrate homeostasis, since it is almost all used by cells as an energy source, or for the synthesis of lipids and other specific functions, i.e., citration of the extracellular matrix by the osteoblasts. In fact, the bulk stored in bone is the main endogenous source of citrate which becomes available following the resorption of the mineralised matrix by the osteoclasts. The mitochondrial citrate-transport protein (CTP) is essential for the release of citrate from the mitochondria to cytosol.
Figure 3
Figure 3
Citrate in the formation of the mineral matrix. The figure combines the theories proposed by different authors regarding the role of citrate in the mineralisation process [38,40,43,44,45]. (A) The amorphous calcium-phosphate (CaP) phase originates from an oversaturated CaP solution, and the mineralisation process starts when the organic phase (citrate, collagen fibrils, and noncollagenous proteins) is available in the bone microenvironment. (B) At the early stage, few citrate molecules bind with the amorphous CaP and the particle aggregation is slowed down. (C) In the next phase, the noncollagenous proteins released from bone cells favour CaP aggregation and apatite nucleation while the collagen promotes the self-assembly of CaP and guides the aggregate deposition on the collagen surface. (D) When the surface is fully covered by citrate, the thickness increase is inhibited (2–6 nm), while longitudinal growth continues up to 30–50 nm, thus explaining the flat morphology of bone mineral platelets. In addition, citrate forms bridges between the mineral platelets which can explain the stacked arrangement which is relevant to the mechanical properties of bone.
Figure 4
Figure 4
Citrate metabolism, osteoblast differentiation, and mineralisation process. The figure combines the concept of “osteoblast citration” with the main steps of the differentiation of mesenchymal stem cells (MSCs) into bone-forming cells (osteoblasts) [5,53,56]. (A) Resting MSCs are quiescent, nonproliferating cells which exhibit the typical mitochondrial metabolism with the oxidation of citrate via the Krebs cycle. (B) In the presence of proper stimuli, the undifferentiated MSCs are committed to osteogenic differentiation and, at the early phase, high proliferation is required. To accomplish this goal, the following events are necessary: (1) the upregulation of ZIP1 which promotes the zinc intake, (2) the accumulation of mitochondrial citrate due to the zinc-dependent inhibition of the mitochondrial aconitase, (3) the exportation of citrate into cytosol by means of the “citrate transport protein” (CTP/SLC25A1), (4) the use of cytosol citrate for the lipogenesis process which is essential for cell duplication. (C,D) The citrate exportation from cytosol to extracellular fluid starts during cell differentiation, and it is simultaneous for the synthesis and the release of amorphous CaP, collagen, and noncollagenous proteins. (E) The “osteoblast citration” is completed when the mineralised matrix is assembled. The role of citrate in growing the apatite nanocrystals and driving the mineralisation process is explained in Figure 3.
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References

    1. Krebs H.A., Johnson W.A. The role of citric acid in intermediate metabolism in animal tissues. FEBS Lett. 1980;117(Suppl. 1):K1–K10. doi: 10.1016/0014-5793(80)80564-3. - DOI - PubMed
    1. [(accessed on 4 July 2019)]; Available online: https://www.genome.jp/kegg-bin/show_pathway?map00020.
    1. Iacobazzi V., Infantino V. Citrate—New functions for an old metabolite. Biol. Chem. 2014;395:387–399. doi: 10.1515/hsz-2013-0271. - DOI - PubMed
    1. Mycielska M.E., Milenkovic V.M., Wetzel C.H., Rümmele P., Geissler E.K. Extracellular Citrate in Health and Disease. Curr. Mol. Med. 2015;15:884–891. doi: 10.2174/1566524016666151123104855. - DOI - PubMed
    1. Franklin R.B., Chellaiah M., Zou J., Reynolds M.A., Costello L.C. Evidence that Osteoblasts are Specialized Citrate-producing Cells that Provide the Citrate for Incorporation into the Structure of Bone. Open Bone J. 2014;6:1–7. doi: 10.2174/1876525401406010001. - DOI - PMC - PubMed

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