Bone and plasma citrate is reduced in osteoporosis

Chen, Hongdong; Wang, Yeyang; Dai, Huaiqian; Tian, Xinggui; Cui, Zhong‐Kai; Chen, Zhenguo; Hu, Le; Song, Qiancheng; Liu, Anling; Zhang, Zhiyong; Xiao, Guozhi; Yang, Jian; Jiang, Yu; Bai, Xiaochun

doi:10.1016/j.bone.2018.06.014

Cited by 49 publications

(49 citation statements)

References 44 publications

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“…In a study published recently, citrate levels were found to be considerably higher in young (mean age 18.8 years) versus older (mean age 64.5 years) males, which is expected given bone turnover (as reflected by b-CTX) was over twofold higher in the former group. (21) However, in a further analysis based on 87 older mixed subjects, there was only weak evidence of an inverse association between serum citrate and turnover markers including b-CTX. (21) Moreover, the authors found citrate to be positively related to both lumbar spine and hip BMD in this group.…”

Section: Discussionmentioning

confidence: 90%

“…(21) However, in a further analysis based on 87 older mixed subjects, there was only weak evidence of an inverse association between serum citrate and turnover markers including b-CTX. (21) Moreover, the authors found citrate to be positively related to both lumbar spine and hip BMD in this group. Although this may suggest that the relationship between citrate and BMD reported here is modified with age, it should be noted that in contrast to BMD C , DXA-derived BMD represents an "areal" density, and as such is affected by skeletal size as reflected PC, which we found to be positively related to citrate levels.…”

Section: Discussionmentioning

confidence: 90%

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A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Kemp

Sayers

Fraser

et al. 2019

Journal of Bone and Mineral Research

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Observations that insulin and adiponectin levels are related to cortical bone size in adolescents, independently of body composition, suggest factors related to fat metabolism directly influence skeletal development. To explore this question, we examined associations between a metabolic screen focusing on fat metabolism, and peripheral quantitative computed tomography (pQCT) measures of the mid‐tibia, in 15‐year‐olds from the Avon Longitudinal Study of Parents and Children. Metabolic profiles were generated by proton nuclear magnetic resonance spectroscopy, from blood samples obtained at the same time as pQCT scans. Ordinary least squares linear regression was used to investigate relationships between metabolic measures and periosteal circumference (PC), cortical thickness (CT), and cortical bone mineral density (BMDC). Metabolic profiles yielded 22 independent components following principal component analysis (PCA), giving a Bonferroni‐adjusted threshold for statistical significance of p = 0.002. Data were available in 1121 subjects (487 males), mean age 15 years. Several metabolites related to lipid and cholesterol metabolism were associated with PC, CT, and BMDC after adjustment for age, sex, and Tanner stage. After additional adjustment for height, fat, and lean mass, only the association between citrate and BMDC remained below the Bonferroni‐significant threshold (β = –0.14 [–0.18, –0.09]) (β represents a standardized coefficient). Citrate also showed evidence of association with PC (β = 0.06 [0.03, 0.10]) and strength strain index (SSI; β = 0.04 [0.01, 0.08]). Subsequently, we investigated whether these relationships were explained by increased bone resorption. Citrate was strongly related to serum β‐C‐telopeptides of type I collagen (β‐CTX) (β = 0.20 [0.16, 0.23]). After additional adjustment for β‐CTX the above associations between citrate and BMDC (β = –0.04 [–0.08, 0.01]), PC (β = 0.03 [–0.01, 0.07]) and SSI (β = 0.03 [–0.01, 0.07]) were no longer observed. We conclude that in adolescents, circulating levels of citrate are inversely related to BMDC and positively related to PC, reflecting associations with higher bone turnover. Further studies are justified to elucidate possible contributions of citrate, a constituent of bone matrix, to bone resorption and cortical density. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Kemp

Sayers

Fraser

et al. 2019

Journal of Bone and Mineral Research

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“…In fact, any factor that diminishes cell energy production, whether through inhibiting the uptake of glucose, glutamine (4,5), or citrate, as demonstrated in the present study, restricting oxygen for oxidative respiration (3), or decreasing the direct substrate for ATP synthesis (e.g., inorganic phosphate) (37), may impair bone formation by inhibiting energy-consuming activities. Given that serum and bone citrate has recently been found to be markedly reduced in aged and osteoporotic patients (38) and that potassium citrate supplementation, previously considered a buffering agent for diet acid loads, sustainably improves bone mass and density, the possibility that systemically administrated citrate could contribute to elevated bone energy status and thus be a potential therapeutic method in bone diseases is worthy of further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…3B), suggesting that hMSCs exhibit a higher demand for exogenous citrate during pre-and early-stage differentiation (toward Runx2 expression, protein synthesis, and so forth) when their primary energy production is via glycolysis, typically without the production of large amounts of endogenous citrate. In contrast, cell metabolism gradually shifts to oxidative phosphorylation in the later stages of osteodifferentiation, generating endogenous citrate via the TCA cycle (18,38,39) while binding exogenous citrate via the extracellular calcium nodules; together, these processes may account for the decreased influence of exogenous citrate on late-stage cell energy metabolism and eventually on osteodifferentiation. The metabonegenic mechanism may be worthy of future study to explore whether nutrient-or energysensing pathways (e.g., the mTOR and the AMPK pathways) are involved in citrate metabonegenic regulation, especially since citrate uptake increased mTOR-dependent protein synthesis and diminished the hypothalamic AMPK activity following exogenous supplementation (40).…”

Section: Discussionmentioning

confidence: 99%

Citrate-based materials fuel human stem cells by metabonegenic regulation

Tian

Kim

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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107

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A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.

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“…Viceversa, nel processo di costruzione delle lamelle ossee gli osteoblasti utilizzano il citrato che viene generato dal metabolismo cellulare (10)(11)(12). Il bilancio tra la quota di citrato rilasciata dallo scheletro e quella che viene usata per la sua costituzione dipende dalla disponibilità di citrato e dalle condizioni del rimodellamento osseo ed è possibile che il pool scheletrico di citrato diminuisca nel corso della vita soprattutto nei soggetti osteoporotici (13).…”

Section: Citrato E Rimodellamento Osseounclassified

Ruolo del citrato nel metabolismo osseo

et al. 2020

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Citrate is an organic compound involved in tricarboxylic acid cycle, regulation of acid-base balance, lipid metabolism and bone formation. The 90% of body citrate is deposited in bone tissue and is released with calcium ions during bone resorption; therefore, bone resorption contributes to maintain normal plasma levels of citrate together with kidney excretion. The parallel release of citrate and calcium from bones decreases the possibility of calcium-phosphate precipitation in soft tissues, as citrate can bind calcium ions in organic fluids. Citrate may also take part to the bone formation as it sustains the correct mineralization of bone organic matrix: its molecule binds calcium ions at the surface of hydroxyapatite nanocrystals and maintains the correct spatial disposition of nanocrystals, thus, stabilizing the structure of bone lamellae and sustaining biomechanical characteristics of bone tissue. Multiple studies observed that citrate administration significantly increased areal and volumetric bone mineral density at different locations of 1-2% per year and improved bone resorption markers as well. Therefore, it has been hypothesised a therapeutic role of citrate in osteoporosis; however, this role has to be better clarified to understand its real anti-fracture effect.

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Bone and plasma citrate is reduced in osteoporosis

Cited by 49 publications

References 44 publications

A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density

Citrate-based materials fuel human stem cells by metabonegenic regulation

Ruolo del citrato nel metabolismo osseo

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