Fibroblast growth-factor 23-Klotho axis is associated with systemic inflammation and myokine profile in children with chronic kidney disease.
FGF23
Follistatin
IGF-1
IL-6
Klotho
Mineral bone disorders
Muscle
Myostatin
Journal
Hormones (Athens, Greece)
ISSN: 2520-8721
Titre abrégé: Hormones (Athens)
Pays: Switzerland
ID NLM: 101142469
Informations de publication
Date de publication:
07 Aug 2024
07 Aug 2024
Historique:
received:
14
11
2023
accepted:
16
07
2024
medline:
8
8
2024
pubmed:
8
8
2024
entrez:
7
8
2024
Statut:
aheadofprint
Résumé
Chronic kidney disease is linked to a disturbed fibroblast growth factor-23 (FGF23)-Klotho axis and an imbalance between myostatin and insulin-like growth factor-1 (IGF-1) expression. This cross-sectional study investigates the association of the FGF23-Klotho axis and myokine profile with serum interleukin-6 (IL-6) and their interactions in pediatric patients. Serum calcium, phosphorus, 25-hydroxyvitamin D, parathormone, c-terminal FGF23, a-Klotho, myostatin, follistatin, IGF-1, and IL-6 were measured in 53 patients with GFR < 60 ml/min/1,73m Myostatin, IGF-1, and follistatin were correlated to LM (rs = 0.513, p < 0.001, rs = 0.652, p < 0.001, rs=-0.483, p < 0.001). Myostatin and follistatin were correlated to IGF-1 (rs = 0.340, p = 0.014, rs=-0.385, p = 0.005). Myostatin/LM but not myostatin or myostatin/IGF-1 ratio was significantly higher in CKD 5D patients (p = 0.001,p = 0.844, p = 0.111). Among mineral bone parameters, lnFGF23 was correlated to lnIL-6 (rs = 0.397, p = 0.004) and associated with high IL-6 (OR 1.905, 95% CI 1.023-3.548). Among myokines, myostatin/IGF-1 ratio was correlated to lnIL-6 (rs = 0.395, p = 0.004) and associated with high IL-6 (OR 1.113, 95% CI 1.028-1.205). All associations were adjusted to CKD stage. Myostatin was correlated to lnFGF23 (rs = 0.331, p = 0.025) and myostatin/IGF-1 ratio to lnKlotho (rs=-0.363, p = 0.013), after adjustment for CKD stage, lnIL-6 and other mineral bone parameters. In pediatric CKD, FGF23 and myostatin/IGF-1 ratio are associated with IL-6, indicating a link between systemic inflammation, mineral bone, and myokine disorders. The correlations between myostatin and FGF23 and between myostatin/IGF-1 and Klotho suggest an interaction between mineral bone and muscle metabolism.
Sections du résumé
BACKGROUND
BACKGROUND
Chronic kidney disease is linked to a disturbed fibroblast growth factor-23 (FGF23)-Klotho axis and an imbalance between myostatin and insulin-like growth factor-1 (IGF-1) expression. This cross-sectional study investigates the association of the FGF23-Klotho axis and myokine profile with serum interleukin-6 (IL-6) and their interactions in pediatric patients.
METHODS
METHODS
Serum calcium, phosphorus, 25-hydroxyvitamin D, parathormone, c-terminal FGF23, a-Klotho, myostatin, follistatin, IGF-1, and IL-6 were measured in 53 patients with GFR < 60 ml/min/1,73m
RESULTS
RESULTS
Myostatin, IGF-1, and follistatin were correlated to LM (rs = 0.513, p < 0.001, rs = 0.652, p < 0.001, rs=-0.483, p < 0.001). Myostatin and follistatin were correlated to IGF-1 (rs = 0.340, p = 0.014, rs=-0.385, p = 0.005). Myostatin/LM but not myostatin or myostatin/IGF-1 ratio was significantly higher in CKD 5D patients (p = 0.001,p = 0.844, p = 0.111). Among mineral bone parameters, lnFGF23 was correlated to lnIL-6 (rs = 0.397, p = 0.004) and associated with high IL-6 (OR 1.905, 95% CI 1.023-3.548). Among myokines, myostatin/IGF-1 ratio was correlated to lnIL-6 (rs = 0.395, p = 0.004) and associated with high IL-6 (OR 1.113, 95% CI 1.028-1.205). All associations were adjusted to CKD stage. Myostatin was correlated to lnFGF23 (rs = 0.331, p = 0.025) and myostatin/IGF-1 ratio to lnKlotho (rs=-0.363, p = 0.013), after adjustment for CKD stage, lnIL-6 and other mineral bone parameters.
CONCLUSIONS
CONCLUSIONS
In pediatric CKD, FGF23 and myostatin/IGF-1 ratio are associated with IL-6, indicating a link between systemic inflammation, mineral bone, and myokine disorders. The correlations between myostatin and FGF23 and between myostatin/IGF-1 and Klotho suggest an interaction between mineral bone and muscle metabolism.
Identifiants
pubmed: 39112785
doi: 10.1007/s42000-024-00586-3
pii: 10.1007/s42000-024-00586-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.
Références
Karava V, Dotis J, Christoforidis A, Kondou A, Printza N (2020) Muscle-bone axis in children with chronic kidney disease: current knowledge and future perspectives. Pediatr Nephrol 36:3813–3327
doi: 10.1007/s00467-021-04936-w
Sun DF, Chen Y, Rabkin R (2006) Work-induced changes in skeletal muscle IGF-1 and myostatin gene expression in uremia. Kidney Int 70:453–459
pubmed: 16871256
doi: 10.1038/sj.ki.5001532
Bataille S, Chauveau P, Fouque D, Aparicio M, Koppe L (2021) Myostatin and muscle atrophy during chronic kidney disease. Nephrol Dial Transpl 36:1986–1993
doi: 10.1093/ndt/gfaa129
Karava V, Dotis J, Christoforidis A, Liakopoulos V, Kondou A, Tsigaras G, Tsioni K, Kollios K, Printza N (2021) Association between insulin growth factor-1, bone mineral density, and frailty phenotype in children with chronic kidney disease. Pediatr Nephrol 36:1861–1870
pubmed: 33598823
doi: 10.1007/s00467-021-04918-y
Karava V, Goutou S, Dotis J, Kondou A, Charela E, Dadoudi O, Eleftheriadis T, Stefanidis I, Printza N (2022) Fatigue and quality of life in children with chronic kidney disease. Child (Basel) 9:1414
Meza K, Biswas S, Zhu YS, Gajjar A, Perelstein E, Kumar J, Akchurin O (2021) Tumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease. Pediatr Nephrol 36:1579–1587
pubmed: 33387018
doi: 10.1007/s00467-020-04846-3
Yamamura-Miyazaki N, Michigami T, Ozono K, Yamamoto K, Hasuike Y (2022) Factors associated with 1-year changes in serum fibroblast growth factor 23 levels in pediatric patients with chronic kidney disease. Clin Exp Nephrol 26:1014–1021
pubmed: 35612637
doi: 10.1007/s10157-022-02238-5
Yamada S, Arase H, Yoshida H, Kitamura H, Tokumoto M, Taniguchi M, Hirakata H, Tsuruya K, Nakano T, Kitazono T (2022) Malnutrition-inflammation Complex Syndrome and Bone fractures and Cardiovascular Disease events in patients undergoing hemodialysis: the Q-Cohort study. Kidney Med 4:100408
pubmed: 35386605
pmcid: 8978069
doi: 10.1016/j.xkme.2022.100408
Yamada S, Tsuruya K, Kitazono T, Nakano T (2022) Emerging cross-talks between chronic kidney disease-mineral and bone disorder (CKD-MBD) and malnutrition-inflammation complex syndrome (MICS) in patients receiving dialysis. Clin Exp Nephrol 26:613–629
pubmed: 35353283
pmcid: 9203392
doi: 10.1007/s10157-022-02216-x
Kuro-o M (2009) Klotho and aging. Biochim Biophys Acta 1790:1049–1058
pubmed: 19230844
pmcid: 2743784
doi: 10.1016/j.bbagen.2009.02.005
Prud’homme GJ, Kurt M, Wang Q (2022) Pathobiology of the Klotho Antiaging Protein and therapeutic considerations. Front Aging 3:931331
pubmed: 35903083
pmcid: 9314780
doi: 10.3389/fragi.2022.931331
Ewendt F, Feger M, Föller M (2021) Myostatin regulates the production of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast-like cells. Pflugers Arch 473:969–976
pubmed: 33895875
pmcid: 8164604
doi: 10.1007/s00424-021-02561-y
Bär L, Feger M, Fajol A, Klotz LO, Zeng S, Lang F, Hocher B, Föller M (2018) Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci U S A 115:5804–5809
pubmed: 29760049
pmcid: 5984514
doi: 10.1073/pnas.1800160115
Rubinek T, Modan-Moses D (2016) Klotho and the growth Hormone/Insulin-Like Growth factor 1 Axis: Novel insights into Complex interactions. Vitam Horm 101:85–118
pubmed: 27125739
doi: 10.1016/bs.vh.2016.02.009
Ohsawa Y, Ohtsubo H, Munekane A, Ohkubo K, Murakami T, Fujino M, Nishimatsu SI, Hagiwara H, Nishimura H, Kaneko R, Suzuki T, Tatsumi R, Mizunoya W, Hinohara A, Fukunaga M, Sunada Y (2023) Circulating α-Klotho counteracts transforming growth Factor-β-Induced Sarcopenia. Am J Pathol 193:591–607
pubmed: 36773783
doi: 10.1016/j.ajpath.2023.01.009
Wolf I, Shahmoon S, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Pinhas-Hamiel O, Yeshayahu Y, Hemi R, Kanety H, Rubinek T, Modan-Moses D (2014) Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment. PLoS ONE 9:e107174
pubmed: 25198618
pmcid: 4157849
doi: 10.1371/journal.pone.0107174
Haffner D, Grund A, Leifheit-Nestler M (2021) Renal effects of growth hormone in health and in kidney disease. Pediatr Nephrol 36:2511–2530
pubmed: 34143299
pmcid: 8260426
doi: 10.1007/s00467-021-05097-6
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637
pubmed: 19158356
pmcid: 2653687
doi: 10.1681/ASN.2008030287
Karava V, Kondou A, Dotis J, Taparkou A, Farmaki E, Kollios K, Printza N (2004) Exploring systemic inflammation in children with chronic kidney disease: correlates of interleukin 6. Pediatr Nephrol 39:1567–1576
doi: 10.1007/s00467-023-06234-z
Choi SJ, Lee MS, Kang DH, Ko GJ, Lim HS, Yu BC, Park MY, Kim JK, Kim CH, Hwang SD, Kim JC, Won CW, An WS (2021) Myostatin/Appendicular Skeletal Muscle Mass (ASM) ratio, not myostatin, is Associated with Low Handgrip Strength in Community-Dwelling Older Women. Int J Environ Res Public Healt 18:7344
doi: 10.3390/ijerph18147344
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135–146
pubmed: 26535997
pmcid: 4854810
doi: 10.1038/ki.2015.290
Egli-Spichtig D, Imenez Silva PH, Glaudemans B, Gehring N, Bettoni C, Zhang MYH, Pastor-Arroyo EM, Schönenberger D, Rajski M, Hoogewijs D, Knauf F, Misselwitz B, Frey-Wagner I, Rogler G, Ackermann D, Ponte B, Pruijm M, Leichtle A, Fiedler GM, Bochud M, Ballotta V, Hofmann S, Perwad F, Föller M, Lang F, Wenger RH, Frew I, Wagner CA (2019) Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation. Kidney Int 96:890–905
pubmed: 31301888
doi: 10.1016/j.kint.2019.04.009
Durlacher-Betzer K, Hassan A, Levi R, Axelrod J, Silver J, Naveh-Many T (2018) Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 94:315–325
pubmed: 29861060
doi: 10.1016/j.kint.2018.02.026
Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, Bazzano LA, Xie D, Kretzler M, Nessel L, Hamm LL, Negrea L, Leonard MB, Raj D, Wolf M, Chronic Renal Insufficiency Cohort (2012) Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol 7:1155–1162
pubmed: 22554719
pmcid: 3386678
doi: 10.2215/CJN.13281211
Navarro-González JF, Mora-Fernández C, Muros M, Herrera H, García J (2009) Mineral metabolism and inflammation in chronic kidney Disease patients: a cross-sectional study. Clin J Am Soc Nephrol 4:1646–1654
pubmed: 19808245
pmcid: 2758261
doi: 10.2215/CJN.02420409
Zhao Y, Banerjee S, Dey N, LeJeune WS, Sarkar PS, Brobey R, Rosenblatt KP, Tilton RG, Choudhary S (2011) Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes 60:1907–1916
pubmed: 21593200
pmcid: 3121423
doi: 10.2337/db10-1262
Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J, Ramirez R, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB (2011) The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J Am Soc Nephrol 22:1315–1325
pubmed: 21719790
pmcid: 3137579
doi: 10.1681/ASN.2010101073
Oh HJ, Nam BY, Lee MJ, Kim CH, Koo HM, Doh FM, Han JH, Kim EJ, Han JS, Park JT, Yoo TH, Kang SW, Han DS, Han SH (2015) Decreased circulating klotho levels in patients undergoing dialysis and relationship to oxidative stress and inflammation. Perit Dial Int 35:43–51
pubmed: 24497597
pmcid: 4335927
doi: 10.3747/pdi.2013.00150
Lisowska KA, Storoniak H, Soroczyńska-Cybula M, Maziewski M, Dębska-Ślizień A (2022) Serum levels of α-Klotho, inflammation-related cytokines, and Mortality in Hemodialysis patients. J Clin Med 11:6518
pubmed: 36362746
pmcid: 9656457
doi: 10.3390/jcm11216518
Gamrot Z, Adamczyk P, Świętochowska E, Roszkowska-Bjanid D, Gamrot J, Szczepańska M (2021) Tumour necrosis factor alpha (TNFα) and alpha-klotho (αKL) in children and adolescents with chronic kidney disease (CKD). Endokrynol Pol 72:628–633
doi: 10.5603/EP.a2021.0082
Miyamoto T, Carrero JJ, Qureshi AR, Anderstam B, Heimbürger O, Bárány P, Lindholm B, Stenvinkel P (2011) Circulating follistatin in patients with chronic kidney disease: implications for muscle strength, bone mineral density, inflammation, and survival. Clin J Am Soc Nephrol 6:1001–1008
pubmed: 21350111
pmcid: 3087764
doi: 10.2215/CJN.10511110
Mak RH, Rotwein P (2006) Myostatin and IGF-1 play crucial roles as the dual regulating hormones in the modulation of muscle mass. Kidney Int 70:410–412
pubmed: 16871252
doi: 10.1038/sj.ki.5001622
Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, Ishima Y, Kotani S, Nakajima M, Tanaka M, Matsushita K, Fukagawa M, Otagiri M, Maruyama T (2016) Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep 6:32084
pubmed: 27549031
pmcid: 4994088
doi: 10.1038/srep32084
Zhang L, Rajan V, Lin E, Hu Z, Han HQ, Zhou X, Song Y, Min H, Wang X, Du J, Mitch WE (2011) Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J 25:1653–1663
pubmed: 21282204
pmcid: 3079306
doi: 10.1096/fj.10-176917
Wilkes JJ, Lloyd DJ, Gekakis N (2009) Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance. Diabetes 58:1133–1143
pubmed: 19208906
pmcid: 2671051
doi: 10.2337/db08-0245
Yasar E, Tek NA, Tekbudak MY, Yurtdaş G, Gülbahar Ö, Uyar GÖ, Ural Z, Çelik ÖM, Erten Y (2022) The relationship between myostatin, inflammatory markers, and Sarcopenia in patients with chronic kidney disease. J Ren Nutr 32:677–684
pubmed: 35122995
doi: 10.1053/j.jrn.2022.01.011
Bish LT, George I, Maybaum S, Yang J, Chen JM, Sweeney HL (2011) Myostatin is elevated in congenital heart disease and after mechanical unloading. PLoS ONE 6:e23818
pubmed: 21931616
pmcid: 3172210
doi: 10.1371/journal.pone.0023818
Witkowska-Sędek E, Pyrżak B (2020) Chronic inflammation and the growth hormone/insulin-like growth factor-1 axis. Cent J Immunol 45:469–475
doi: 10.5114/ceji.2020.103422
Mak RH, Gunta S, Oliveira EA, Cheung WW (2022) Growth hormone improves adipose tissue Browning and muscle wasting in mice with chronic kidney Disease-Associated Cachexia. Int J Mol Sci 23:15310
pubmed: 36499637
pmcid: 9740214
doi: 10.3390/ijms232315310
Garcia LA, King KK, Ferrini MG, Norris KC, Artaza JN (2011) 1,25(OH)2vitamin D3 stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells. Endocrinology 152:2976–2986
pubmed: 21673099
pmcid: 3138228
doi: 10.1210/en.2011-0159
Ameri P, Giusti A, Boschetti M, Murialdo G, Minuto F, Ferone D (2013) Interactions between vitamin D and IGF-I: from physiology to clinical practice. Clin Endocrinol (Oxf) 79:457–463
pubmed: 23789983
doi: 10.1111/cen.12268
Elsurer Afsar R, Afsar B, Ikizler TA (2023) Fibroblast growth factor 23 and muscle wasting: a metabolic point of View. Kidney Int Rep 8:1301–1314
pubmed: 37441473
pmcid: 10334408
doi: 10.1016/j.ekir.2023.04.027
Karava V, Christoforidis A, Kondou A, Dotis J, Printza N (2021) Update on the Crosstalk between adipose tissue and Mineral Balance in General Population and chronic kidney disease. Front Pediatr 9:696942
pubmed: 34422722
pmcid: 8378583
doi: 10.3389/fped.2021.696942
Avin KG, Coen PM, Huang W, Stolz DB, Sowa GA, Dubé JJ, Goodpaster BH, O’Doherty RM, Ambrosio F (2014) Skeletal muscle as a regulator of the longevity protein. Klotho Front Physiol 5:189
pubmed: 24987372
Jovanovich A, Ginsberg C, You Z, Katz R, Ambrosius WT, Berlowitz D, Cheung AK, Cho M, Lee AK, Punzi H, Rehman S, Roumie C, Supiano MA, Wright CB, Shlipak M, Ix JH, Chonchol M (2021) FGF23, Frailty, and Falls in SPRINT. J Am Geriatr Soc 69:467–473
pubmed: 33289072
doi: 10.1111/jgs.16895
Veronesi F, Borsari V, Cherubini A, Fini M (2021) Association of Klotho with physical performance and frailty in middle-aged and older adults: a systematic review. Exp Gerontol 154:111518
pubmed: 34407459
doi: 10.1016/j.exger.2021.111518
Liu W, Thomas SG, Asa SL, Gonzalez-Cadavid N, Bhasin S, Ezzat S (2003) Myostatin is a skeletal muscle target of growth hormone anabolic action. J Clin Endocrinol Metab 88:5490–5496
pubmed: 14602795
doi: 10.1210/jc.2003-030497
Rubinek T, Shahmoon S, Shabtay-Orbach A, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Yeshayahu Y, Doolman R, Hemi R, Kanety H, Wolf I, Modan-Moses D (2016) Klotho response to treatment with growth hormone and the role of IGF-I as a mediator. Metabolism 65:1597–1604
pubmed: 27733247
doi: 10.1016/j.metabol.2016.08.004