Plasma midkine concentrations in healthy children, children with increased and decreased adiposity, and children with short stature

Autoři: Youn Hee Jee aff001;  Kun Song Lee aff002;  Shanna Yue aff001;  Ellen W. Leschek aff003;  Matthew G. Boden aff001;  Aysha Jadra aff001;  Anne Klibanski aff004;  Priya Vaidyanathan aff005;  Madhusmita Misra aff004;  Young Pyo Chang aff002;  Jack A. Yanovski aff001;  Jeffrey Baron aff001
Působiště autorů: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America aff001;  Pediatrics, Dankook University Hospital, Cheonan, Republic of Korea aff002;  National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States of America aff003;  Division of Pediatric Endocrinology, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, United States of America aff004;  Pediatric Endocrinology, Children’s National Medical Center, Washington, DC, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224103



Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied.

Subjects and methods

Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0–18 yrs, 101 boys), 206 healthy adults (age 18–91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4–18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14–23 yrs), and 75 children with idiopathic short stature (age 3–18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated.


In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS.


In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.

Klíčová slova:

Adipose tissue – Anorexia nervosa – Blood plasma – Body mass index – Growth hormone – Child health – Childhood obesity – Children


1. Muramatsu T. Midkine (MK), the product of a retinoic acid responsive gene, and pleiotrophin constitute a new protein family regulating growth and differentiation. Int J Dev Biol. 1993. 37(1):183–8. 8507561

2. Zou K, Muramatsu H, Ikematsu S, Sakuma S, Salama RH, Shinomura T, et al. A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican. Eur J Biochem. 2000. 267(13):4046–53. doi: 10.1046/j.1432-1327.2000.01440.x 10866805

3. Muramatsu T. Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem. 2002 Sep;132(3):359–71. doi: 10.1093/oxfordjournals.jbchem.a003231 12204104

4. Ikematsu S, Yano A, Aridome K, Kikuchi M, Kumai H, Nagano H, et al. Serum midkine levels are increased in patients with various types of carcinomas. Br J Cancer. 2000 Sep;83(6):701–6. doi: 10.1054/bjoc.2000.1339 10952771

5. Jones DR. Measuring midkine: the utility of midkine as a biomarker in cancer and other diseases. Br J Pharmacol. 2014. 171(12):2925–39. doi: 10.1111/bph.12601 24460734

6. Jee YH, Celi FS, Sampson M, Sacks DB, Remaley AT, Kebebew E, et al. Midkine concentrations in fine-needle aspiration of benign and malignant thyroid nodules. Clin Endocrinol (Oxf). 2015. 83(6):977–84.

7. Olmeda D, Cerezo-Wallis D, Riveiro-Falkenbach E, Pennacchi PC, Contreras-Alcalde M, Ibarz N, et al. Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. Nature. 2017. 28;546(7660):676–680. doi: 10.1038/nature22977 28658220

8. Ikematsu S, Nakagawara A, Nakamura Y, Sakuma S, Wakai K, Muramatsu T, et al. Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas. Br J Cancer. 2003. 19;88(10):1522–6. doi: 10.1038/sj.bjc.6600938 12771916

9. Ibusuki M, Fujimori H, Yamamoto Y, Ota K, Ueda M, Shinriki S, et al. Midkine in plasma as a novel breast cancer marker. Cancer Sci. 2009. 100(9):1735–9. doi: 10.1111/j.1349-7006.2009.01233.x 19538527

10. Yamashita T, Shimada H, Tanaka S, Araki K, Tomifuji M, Mizokami D, et al. Serum midkine as a biomarker for malignancy, prognosis, and chemosensitivity in head and neck squamous cell carcinoma. Cancer Med. 2016. 5(3):415–25. doi: 10.1002/cam4.600 26798989

11. Zhu WW, Guo JJ, Guo L, Jia HL, Zhu M, Zhang JB, et al. Evaluation of midkine as a diagnostic serum biomarker in hepatocellular carcinoma. Clin Cancer Res. 2013. 15;19(14):3944–54. doi: 10.1158/1078-0432.CCR-12-3363 23719264

12. Lucas S, Reindl T, Henze G, Kurtz A, Sakuma S, Driever PH. Increased midkine serum levels in pediatric embryonal tumor patients. J Pediatr Hematol Oncol. 2009. 31(10):713–7. doi: 10.1097/MPH.0b013e3181b6db9f 19727009

13. Mitsiadis TA, Salmivirta M, Muramatsu T, Muramatsu H, Rauvala H, Lehtonen E, et al. Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis. Development. 1995. 121(1):37–51. 7867507

14. Mitsiadis TA, Muramatsu T, Muramatsu H, Thesleff I. Midkine (MK), a heparin-binding growth/differentiation factor, is regulated by retinoic acid and epithelial-mesenchymal interactions in the developing mouse tooth, and affects cell proliferation and morphogenesis. J Cell Biol. 1995. 129(1):267–81. doi: 10.1083/jcb.129.1.267 7698992

15. Lui JC, Forcinito P, Chang M, Chen W, Barnes KM, Baron J. Coordinated postnatal down-regulation of multiple growth-promoting genes: evidence for a genetic program limiting organ growth. FASEB J. 2010. 24(8):3083–92. doi: 10.1096/fj.09-152835 20371622

16. Delaney A, Padmanabhan V, Rezvani G, Chen W, Forcinito P, Cheung CS, et al. Evolutionary conservation and modulation of a juvenile growth-regulating genetic program. J Mol Endocrinol. 2014. 28;52(3):269–77. doi: 10.1530/JME-13-0263 24776848

17. Zou P, Muramatsu H, Sone M, Hayashi H, Nakashima T, Muramatsu T. Mice doubly deficient in the midkine and pleiotrophin genes exhibit deficits in the expression of beta-tectorin gene and in auditory response. Lab Invest. 2006. 86(7):645–53. doi: 10.1038/labinvest.3700428 16619002

18. Fan N, Sun H, Wang Y, Zhang L, Xia Z, Peng L, Hou Y, et al. Midkine, a potential link between obesity and insulin resistance. PLoS One. 2014. 7;9(2):e88299. doi: 10.1371/journal.pone.0088299 24516630

19. Lucas S, Henze G, Schnabel D, Barthlen W, Sakuma S, Kurtz A, et al. Serum levels of Midkine in children and adolescents without malignant disease. Pediatr Int. 2010. 52(1):75–9. doi: 10.1111/j.1442-200X.2009.02885.x 19460128

20. Singhal V, Tulsiani S, Campoverde KJ, Mitchell DM, Slattery M, Schorr M, et al. Impaired bone strength estimates at the distal tibia and its determinants in adolescents with anorexia nervosa. Bone. 2018 Jan;106:61–68. doi: 10.1016/j.bone.2017.07.009 28694162

21. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, et al. CDC growth charts: United States. Adv Data. 2000. 8;(314):1–27. 11183293

22. Must A, Anderson SE. Body mass index in children and adolescents: considerations for population-based applications. Int J Obes (Lond). 2006. 30(4):590–4.

23. Jee YH, Lebenthal Y, Chaemsaithong P, Yan G, Peran I, Wellstein A, et al. Midkine and Pleiotrophin Concentrations in Amniotic Fluid in Healthy and Complicated Pregnancies. PLoS One. 2016. 18;11(4):e0153325. doi: 10.1371/journal.pone.0153325 27089523

24. Muramatsu H, Zou P, Kurosawa N, Ichihara-Tanaka K, Maruyama K, Inoh K, et al. Female infertility in mice deficient in midkine and pleiotrophin, which form a distinct family of growth factors. Genes Cells. 2006 Dec;11(12):1405–17. doi: 10.1111/j.1365-2443.2006.01028.x 17121547

25. Hando A, Takesima S, Takahama M, Itoh S, Yokoo T, Kasai M, et al. 2008. [Pre-analytical problems on assay conditions for blood midkine]. Rinsho Byori 56:221–227. 18411806

26. Hung YJ, Lin ZH, Cheng TI, Liang CT, Kuo TM, Kao KJ. Serum midkine as a prognostic biomarker for patients with hepatocellular carcinoma. Am J Clin Pathol. 2011. 136(4): 594–603. doi: 10.1309/AJCPWT70XOVXSVGE 21917682

Článek vyšel v časopise


2019 Číslo 10