Journal of Endocrinological Investigation

, Volume 42, Issue 12, pp 1477–1483 | Cite as

p38MAPK controls fibroblast growth factor 23 (FGF23) synthesis in UMR106-osteoblast-like cells and in IDG-SW3 osteocytes

  • F. Ewendt
  • M. FöllerEmail author
Original Article



p38 mitogen-activated protein kinase (p38MAPK) is a serine/threonine kinase activated by cellular stress stimuli including radiation, osmotic shock, and inflammation and influencing apoptosis, cell proliferation, and autophagy. Moreover, p38MAPK induces transcriptional activity of the transcription factor complex NFκB mediating multiple pro-inflammatory cellular responses. Fibroblast growth factor 23 (FGF23) is produced by bone cells, and regulates renal phosphate and vitamin D metabolism as a hormone. FGF23 expression is enhanced by NFκB. Here, we analyzed the relevance of p38MAPK activity for the production of FGF23.


Fgf23 expression was analyzed by qRT-PCR and FGF23 protein by ELISA in UMR106 osteoblast-like cells and in IDG-SW3 osteocytes.


Inhibition of p38MAPK with SB203580 or SB202190 significantly down-regulated Fgf23 expression and FGF23 protein expression. Conversely, p38MAPK activator anisomycin increased the abundance of Fgf23 mRNA. NFκB inhibitors wogonin and withaferin A abrogated the stimulatory effect of anisomycin on Fgf23 gene expression.


p38MAPK induces FGF23 formation, an effect at least in part dependent on NFκB activity.


Anisomycin NFκB Calcium Phosphate Klotho 



The authors acknowledge the technical assistance of S. Ross and F. Reipsch.


This study was supported by the Deutsche Forschungsgemeinschaft [Fo 695/2-1].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not required in this type of study.


  1. 1.
    Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429(3):403–417. CrossRefPubMedGoogle Scholar
  2. 2.
    Cuenda A, Rousseau S (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773(8):1358–1375. CrossRefPubMedGoogle Scholar
  3. 3.
    Wang Y, Liu L, Zhou D (2011) Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury. Radiat Res 176(6):743–752CrossRefGoogle Scholar
  4. 4.
    Gatidis S, Zelenak C, Fajol A et al (2011) p38 MAPK activation and function following osmotic shock of erythrocytes. Cell Physiol Biochem 28(6):1279–1286. CrossRefPubMedGoogle Scholar
  5. 5.
    Sreekanth GP, Chuncharunee A, Sirimontaporn A et al (2016) SB203580 modulates p38 MAPK signaling and dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One 11(2):e0149486. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bonney EA (2017) Mapping out p38MAPK. Am J Reprod Immunol. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Risco A, Cuenda A (2012) New insights into the p38γ and p38δ MAPK pathways. J Signal Transduct 2012:520289. CrossRefPubMedGoogle Scholar
  8. 8.
    Cai B, Chang SH, Becker EBE et al (2006) p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 281(35):25215–25222. CrossRefPubMedGoogle Scholar
  9. 9.
    Kralova J, Dvorak M, Koc M et al (2008) p38 MAPK plays an essential role in apoptosis induced by photoactivation of a novel ethylene glycol porphyrin derivative. Oncogene 27(21):3010–3020. CrossRefPubMedGoogle Scholar
  10. 10.
    Sui X, Kong N, Ye L et al (2014) p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett 344(2):174–179. CrossRefPubMedGoogle Scholar
  11. 11.
    Ventura JJ, Tenbaum S, Perdiguero E et al (2007) p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet 39(6):750–758. CrossRefPubMedGoogle Scholar
  12. 12.
    Cong Q, Jia H, Li P et al (2017) p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner. Sci Rep 7:45964. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang X, Goh CH, Li B (2007) p38 mitogen-activated protein kinase regulates osteoblast differentiation through osterix. Endocrinology 148(4):1629–1637. CrossRefPubMedGoogle Scholar
  14. 14.
    He Y, She H, Zhang T et al (2018) p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1. J Cell Biol 217(1):315–328. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kefaloyianni E, Gaitanaki C, Beis I (2006) ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal 18(12):2238–2251. CrossRefPubMedGoogle Scholar
  16. 16.
    Liu T, Zhang L, Joo D et al (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Olson CM, Hedrick MN, Izadi H et al (2006) p38 mitogen-activated protein kinase controls NF-κB transcriptional activation and tumor necrosis factor alpha production through RelA Phosphorylation Mediated by mitogen- and stress-activated protein kinase 1 in response to borrelia burgdorferi antigens. Infect Immun 75(1):270–277. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Eylenstein A, Schmidt S, Gu S et al (2011) Transcription factor NF-κB regulates expression of pore-forming Ca2+ channel unit, Orai1, and its activator, STIM1, to control Ca2+ entry and affect cellular functions. J Biol Chem 287(4):2719–2730. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Prakriya M (2009) The molecular physiology of CRAC channels. Immunol Rev 231(1):88–98. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Prakriya M (2013) Store-operated Orai channels: structure and function. Curr Top Membr 71:1–32. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Feger M, Hase P, Zhang B et al (2017) The production of fibroblast growth factor 23 is controlled by TGF-β2. Sci Rep 7(1):4982. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Glosse P, Feger M, Mutig K et al (2018) AMP-activated kinase is a regulator of fibroblast growth factor 23 production. Kidney Int 94(3):491–501. CrossRefPubMedGoogle Scholar
  23. 23.
    Zhang B, Umbach AT, Chen H et al (2016) Up-regulation of FGF23 release by aldosterone. Biochem Biophys Res Commun 470(2):384–390. CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang B, Yan J, Umbach AT et al (2016) NFκB-sensitive Orai1 expression in the regulation of FGF23 release. J Mol Med 94(5):557–566. CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang B, Yan J, Schmidt S et al (2015) Lithium-sensitive store-operated Ca2+ entry in the regulation of FGF23 release. Neurosignals 23(1):34–48. CrossRefPubMedGoogle Scholar
  26. 26.
    Boland JM, Tebben PJ, Folpe AL (2018) Phosphaturic mesenchymal tumors: what an endocrinologist should know. J Endocrinol Investig 41(10):1173–1184. CrossRefGoogle Scholar
  27. 27.
    Kamelian T, Saki F, Jeddi M et al (2018) Effect of cholecalciferol therapy on serum FGF23 in vitamin D deficient patients: a randomized clinical trial. J Endocrinol Investig 41(3):299–306. CrossRefGoogle Scholar
  28. 28.
    Saki F, Kasaee SR, Sadeghian F et al (2018) Investigating the effect of testosterone by itself and in combination with letrozole on 1,25-dihydroxy vitamin D and FGF23 in male rats. J Endocrinol Investig 42(1):19–25. CrossRefGoogle Scholar
  29. 29.
    Hu MC, Shiizaki K, Kuro-o M et al (2013) Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75:503–533. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Saini RK, Kaneko I, Jurutka PW et al (2013) 1,25-dihydroxyvitamin D(3) regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. Calcif Tissue Int 92(4):339–353. CrossRefPubMedGoogle Scholar
  31. 31.
    Kuro-o M (2013) Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol 9(11):650–660. CrossRefPubMedGoogle Scholar
  32. 32.
    Shimada T, Kakitani M, Yamazaki Y et al (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Investig 113(4):561–568. CrossRefPubMedGoogle Scholar
  33. 33.
    Raya AI, Rios R, Pineda C et al (2016) Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats. Sci Rep 6:36881. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51. CrossRefPubMedGoogle Scholar
  35. 35.
    Lu X, Hu MC (2016) Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis (Basel) 3(1):15–23. CrossRefGoogle Scholar
  36. 36.
    Faul C (2016) Cardiac actions of fibroblast growth factor 23. Bone 100:69–79. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rossaint J, Oehmichen J, van Aken H et al (2016) FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Investig 126(3):962–974. CrossRefPubMedGoogle Scholar
  38. 38.
    Yang K, Peretz-Soroka H, Wu J et al (2017) Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices. Sci Rep 7(1):3100. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dalton GD, Xie J, An S-W et al (2017) New insights into the mechanism of action of soluble Klotho. Front Endocrinol (Lausanne) 8:323. CrossRefGoogle Scholar
  40. 40.
    Nitta K (2018) Fibroblast growth factor 23 and cardiovascular disease in patients with chronic kidney disease. Ren Replace Ther 4(1):19. CrossRefGoogle Scholar
  41. 41.
    Wahl P, Wolf M (2012) FGF23 in chronic kidney disease. Adv Exp Med Biol 728:107–125. CrossRefPubMedGoogle Scholar
  42. 42.
    Di Giuseppe R, Kühn T, Hirche F et al (2015) Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study. Eur J Epidemiol 30(2):131–141. CrossRefPubMedGoogle Scholar
  43. 43.
    Ozeki M, Fujita S-i, Kizawa S et al (2014) Association of serum levels of FGF23 and α-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol 15:147. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Filler G, Liu D, Huang S-HS et al (2011) Impaired GFR is the most important determinant for FGF-23 increase in chronic kidney disease. Clin Biochem 44(5–6):435–437. CrossRefPubMedGoogle Scholar
  45. 45.
    Chudek J, Kocełak P, Owczarek A et al (2014) Fibroblast growth factor 23 (FGF23) and early chronic kidney disease in the elderly. Nephrol Dial Transplant 29(9):1757–1763. CrossRefPubMedGoogle Scholar
  46. 46.
    Larsson T, Nisbeth U, Ljunggren O et al (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64(6):2272–2279. CrossRefPubMedGoogle Scholar
  47. 47.
    Schnedl C, Fahrleitner-Pammer A, Pietschmann P et al (2015) FGF23 in acute and chronic illness. Dis Mark 2015:358086. CrossRefGoogle Scholar
  48. 48.
    Kolek OI, Hines ER, Jones MD et al (2005) 1Alpha,25-dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal–gastrointestinal–skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289(6):G1036–G1042. CrossRefPubMedGoogle Scholar
  49. 49.
    Krajisnik T, Björklund P, Marsell R et al (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195(1):125–131. CrossRefPubMedGoogle Scholar
  50. 50.
    Lanske B, Razzaque MS (2014) Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int 86(6):1072–1074. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Knab VM, Corbin B, Andrukhova O et al (2017) Acute parathyroid hormone injection increases C-terminal but not intact fibroblast growth factor 23 levels. Endocrinology 158(5):1130–1139. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Sigrist M, Tang M, Beaulieu M et al (2013) Responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD): results of a randomized trial. Nephrol Dial Transplant 28(1):161–169. CrossRefPubMedGoogle Scholar
  53. 53.
    Vervloet MG, van Ittersum FJ, Büttler RM et al (2011) Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin J Am Soc Nephrol 6(2):383–389. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Glosse P, Fajol A, Hirche F et al (2018) A high-fat diet stimulates fibroblast growth factor 23 formation in mice through TNFα upregulation. Nutr Diabetes 8(1):36. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Masuda Y, Ohta H, Morita Y et al (2015) Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. Biol Pharm Bull 38(5):687–693. CrossRefPubMedGoogle Scholar
  56. 56.
    Rossaint J, Unruh M, Zarbock A (2017) Fibroblast growth factor 23 actions in inflammation: a key factor in CKD outcomes. Nephrol Dial Transplant 32(9):1448–1453. CrossRefPubMedGoogle Scholar
  57. 57.
    Wallquist C, Mansouri L, Norrbäck M et al (2018) Associations of fibroblast growth factor 23 with markers of inflammation and leukocyte transmigration in chronic kidney disease. Nephron 138(4):287–295. CrossRefPubMedGoogle Scholar
  58. 58.
    Sharaf El Din UAA, Salem MM, Abdulazim DO (2017) FGF23 and inflammation. World J Nephrol 6(1):57–58. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    David V, Martin A, Isakova T et al (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89(1):135–146. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Wolf M, Koch TA, Bregman DB (2013) Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28(8):1793–1803. CrossRefPubMedGoogle Scholar
  61. 61.
    Bär L, Feger M, Fajol A et al (2018) Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci USA 115(22):5804–5809. CrossRefPubMedGoogle Scholar
  62. 62.
    Woo SM, Rosser J, Dusevich V et al (2011) Cell line IDG-SW3 replicates osteoblast-to-late-osteocyte differentiation in vitro and accelerates bone formation in vivo. J Bone Miner Res 26(11):2634–2646. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Rodríguez-Carballo E, Gámez B, Ventura F (2016) p38 MAPK signaling in osteoblast differentiation. Front Cell Dev Biol 4(21):30476. CrossRefGoogle Scholar
  64. 64.
    Greenblatt MB, Shim J-H, Zou W et al (2010) The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest 120(7):2457–2473. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ge C, Xiao G, Jiang Di et al (2009) Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J Biol Chem 284(47):32533–32543. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mehrotra M, Krane SM, Walters K et al (2004) Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells. J Cell Biochem 93(4):741–752. CrossRefPubMedGoogle Scholar
  67. 67.
    Nam TW, Yoo CI, Kim HT et al (2008) The flavonoid quercetin induces apoptosis and inhibits migration through a MAPK-dependent mechanism in osteoblasts. J Bone Miner Metab 26(6):551–560. CrossRefPubMedGoogle Scholar
  68. 68.
    Zhou FH, Foster BK, Zhou X-F et al (2006) TNF-alpha mediates p38 MAP kinase activation and negatively regulates bone formation at the injured growth plate in rats. J Bone Miner Res 21(7):1075–1088. CrossRefPubMedGoogle Scholar
  69. 69.
    Li X, Udagawa N, Itoh K et al (2002) p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology 143(8):3105–3113. CrossRefPubMedGoogle Scholar
  70. 70.
    Allard L, Demoncheaux N, Machuca-Gayet I et al (2015) Biphasic effects of vitamin D and FGF23 on human osteoclast biology. Calcif Tissue Int 97(1):69–79. CrossRefPubMedGoogle Scholar
  71. 71.
    Chen G, Deng C, Li Y-P (2012) TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8(2):272–288. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Tan Y, Xu Q, Li Y et al (2014) Crosstalk between the p38 and TGF-β signaling pathways through TβRI, TβRII and Smad3 expression in plancental choriocarcinoma JEG-3 cells. Oncol Lett 8(3):1307–1311. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Rey A, Manen D, Rizzoli R et al (2007) Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells. Bone 41(1):59–67. CrossRefPubMedGoogle Scholar
  74. 74.
    Böhm C, Hayer S, Kilian A et al (2009) The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss. J Immunol 183(9):5938–5947. CrossRefPubMedGoogle Scholar
  75. 75.
    Yang H-T, Cohen P, Rousseau S (2008) IL-1beta-stimulated activation of ERK1/2 and p38alpha MAPK mediates the transcriptional up-regulation of IL-6, IL-8 and GRO-alpha in HeLa cells. Cell Signal 20(2):375–380. CrossRefPubMedGoogle Scholar
  76. 76.
    Lee Y-M, Fujikado N, Manaka H et al (2010) IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol 22(10):805–816. CrossRefPubMedGoogle Scholar
  77. 77.
    Yamazaki M, Kawai M, Miyagawa K et al (2015) Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 33(3):342–354. CrossRefPubMedGoogle Scholar
  78. 78.
    Brown KK, Heitmeyer SA, Hookfin EB et al (2008) P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond) 5:22. CrossRefGoogle Scholar
  79. 79.
    Krementsov DN, Thornton TM, Teuscher C et al (2013) The emerging role of p38 mitogen-activated protein kinase in multiple sclerosis and its models. Mol Cell Biol 33(19):3728–3734. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Lee JK, Kim N-J (2017) Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules 22(8):1287. CrossRefPubMedCentralGoogle Scholar
  81. 81.
    Yong H-Y, Koh M-S, Moon A (2009) The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs 18(12):1893–1905. CrossRefPubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Institute of Agricultural and Nutritional SciencesMartin Luther University Halle-WittenbergHalle (Saale)Germany
  2. 2.Institute of PhysiologyUniversity of HohenheimStuttgartGermany

Personalised recommendations