Hyponatremia elicits gene expression changes driving osteoclast differentiation and functions

Barsony, Julianna; Xu, Qin; Verbalis, Joseph G.

doi:10.1016/j.mce.2022.111724

Cited by 7 publications

(6 citation statements)

References 46 publications

(59 reference statements)

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“…However, such drastic changes of [Na + ] occur only in the renal medulla, but not in bone. Now, our findings suggest that even differences of 20-40 mM NaCl significantly regulate NFAT5 activity in osteoblasts and osteoclasts, which is consistent with recent other studies 21,32 . Serum/glucocorticoid regulated kinase 1 (Sgk1) 50 , transient receptor potential vanilloid type 4 (Trpv4) 51 , Na + /K + /ATPase (Atp1a1) and its associated protein such as sucrose non-fermenting-1-related serine/threonine kinase-SIK1 (Snrk) 52 were previously postulated to take part in [Na + ] sensing in various cells.…”

Section: Discussionsupporting

confidence: 93%

“…In line with studies from others 29,30,32 , we found that osteoblasts can sense osmotically relevant changes in [Na + ] and respond with an altered expression of several genes including Fgf23. Studies in RAW264.7 pre-osteoclastic cells showed increased osteoclast formation and resorptive activity in response to low [Na + ] concentration 20,21 . The molecular mechanism by which [Na + ] is detected by bone cells is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Both hyponatremia (serum [Na + ] <135 mM) and hypernatremia (serum [Na + ] >145 mM) can affect bone remodeling. Several studies have provided compelling evidence linking hyponatremia to bone loss, osteoporosis, and heightened bone fragility [19][20][21][22][23][24] . Most hyponatremia cases are due to the syndrome of inappropriate antidiuretic hormone secretion (SIAD), which is characterized by high arginine vasopressin (AVP) levels (reviewed in 25 ).…”

Section: Significance Statementmentioning

confidence: 99%

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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

Radvanyi,

Yoo,

Kandasamy

et al. 2023

Preprint

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Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (low serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that human hyponatremic patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Significance Statementmentioning

confidence: 99%

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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

Radvanyi,

Yoo,

Kandasamy

et al. 2023

Preprint

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“…Because osteoclasts are also activated in a hyponatremic environment in the absence of AVP ( 6 ), an additive independent effects of low sodium and AVP could explain the discrepancy between human data with and without tolvaptan, and animal data. The separate effect of low sodium is shown in studies conducted in vitro in which an increase in osteoclast differentiation ( 6 , 25 ), numbers ( 6 ), and activity ( 6 , 25 ) due to hyponatremia is observed independently of osmolality and AVP ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

An Increase in Plasma Sodium Levels Is Associated With an Increase in Osteoblast Function in Chronic SIAD

Monnerat

Refardt

Potasso

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Hyponatremia is associated with increased risk for osteoporosis. Preclinical studies in untreated hyponatremia suggest osteoclast upregulation whereas a clinical study showed improved osteoblast fuction after hyponatremia normalization in hospitalized patients with syndrome of inappropriate antidiuresis (SIAD). Objective To investigate the impact of sodium increase on bone turnover, i.e. the ratio of the osteoblast marker procollagen type 1 N (P1NP) to the osteoclast marker C-telopeptide crosslink (CTX), in outpatients with chronic SIAD. Design Predefined secondary analysis of the two-month double-blind, crossover, placebo-controlled SANDx Trial (NCT03202667) performed from 12/2017 to 08/2021. Setting and Patients 11 outpatients with chronic SIAD, 6 females, median age 73 years. Intervention 4-week treatment with 25 mg empagliflozin or placebo. Main Outcome Measure Relationship between the change in bone formation index (BFI), defined as P1NP/CTX, and the change in plasma sodium levels. Results Changes in sodium were positively correlated with changes in BFI and P1NP (BFI: ρ=0.55, p < 0.001; P1NP: ρ=0.45, p = 0.004) but not with CTX (p = 0.184) and osteocalcin (p = 0.149). A sodium increase of 1 mmol/L was associated with an increase of 5.21 in BFI (95%-CI: 1.41, 9.00, p = 0.013) and with an increase of 1.48 µg/L in P1NP (95%-CI: 0.26, 2.62, p = 0.03). The effect of sodium change on bone markers was independent of the study medication empagliflozin. Conclusion An increase in plasma sodium levels in outpatients with chronic hyponatremia due to SIAD, even when mild, was associated with an increase in bone formation index (P1NP/CTX) triggered by an increase in P1NP, a surrogate marker of osteoblast function.

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“…Additional intracellular signalling pathways, have been recently identified using ribonucleic acid (RNA) sequencing and gene ontology analysis and include receptor activator of nuclear factor kappa-B ligand, and PI3K/Akt pathways, lysosomal activity and dysregulation of autophagy, mitochondrial energy production, and osteoclast motility [ Figure 1(b) ], further supporting the central role of osteoclasts on the hyponatremia-induced bone loss. 45 Accordingly, hyponatremia also exerts direct effects on human mesenchymal stromal cells (hMSCs), which is the common progenitor for osteoblasts and adipocytes. In an experimental model of hMSCs isolated from the bone marrow of healthy donors, low Na+ levels inhibited cellular adhesion and cellular viability, and disrupted the tubulin organization of the cytoskeleton, leading to an overall disruption of cellular homeostasis.…”

Section: The Pathophysiology Of Hyponatremia-induced Bone Lossmentioning

confidence: 99%

Association of hyponatremia with bone mineral density and fractures: a narrative review

Tzoulis,

Yavropoulou

2023

Therapeutic Advances in Endocrinology

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Recent studies suggest a possible association of hyponatremia with osteoporosis, falls and bone fractures. The objectives of this narrative review were to further explore this association and the related pathophysiological mechanisms and to suggest a practical approach to patients with osteoporosis or chronic hyponatremia in clinical practice. We conducted an extensive PubMed search until October 2022 with the combination of the following keywords: ‘hyponatremia’ or ‘sodium’ or ‘SIADH’ and ‘fractures’ or ‘bone’ or ‘osteoporosis’, as MeSH Terms. Review of numerous observational studies confirms a significant independent association of, even mild, hyponatremia with two- to three-fold increase in the occurrence of bone fractures. Hyponatremia is a risk factor for osteoporosis with a predilection to affect the hip, while the magnitude of association depends on the severity and chronicity of hyponatremia. Chronic hyponatremia also increases the risk for falls by inducing gait instability and neurocognitive deficits. Besides the detrimental impact of hyponatremia on bone mineral density and risk of falls, it also induces changes in bone quality. Emerging evidence suggests that acute hyponatremia shifts bone turnover dynamics towards less bone formation, while hyponatremia correction increases bone formation. The key unanswered question whether treatment of hyponatremia could improve osteoporosis and lower fracture risk highlights the need for prospective studies, evaluating the impact of sodium normalization on bone metabolism and occurrence of fractures. Recommendations for clinical approach should include measurement of serum sodium in all individuals with fracture or osteoporosis. Also, hyponatremia, as an independent risk factor for fracture, should be taken into consideration when estimating the likelihood for future fragility fracture and in clinical decision-making about pharmacological therapy of osteoporosis. Until it is proven that normalization of sodium can lower fracture occurrence, correcting hyponatremia cannot be universally recommended on this basis, but should be decided on a case-by-case basis.

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Hyponatremia elicits gene expression changes driving osteoclast differentiation and functions

Cited by 7 publications

References 46 publications

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

An Increase in Plasma Sodium Levels Is Associated With an Increase in Osteoblast Function in Chronic SIAD

Association of hyponatremia with bone mineral density and fractures: a narrative review

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