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30.04.2019 | Original Article

Activin-A is elevated in patients with thalassemia major and double heterozygous sickle cell/beta-thalassemia and correlates with markers of hemolysis and bone mineral density

verfasst von: Ersi Voskaridou, Ioannis Ntanasis-Stathopoulos, Dimitrios Christoulas, Maria Dimopoulou, Veroniki Komninaka, Konstantina Repa, Athanasios Papatheodorou, Evangelos Terpos

Erschienen in: Annals of Hematology | Ausgabe 7/2019

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Abstract

Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.

Williams TN, Weatherall DJ (2012) World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2(9):a011692. https://doi.org/10.1101/cshperspect.a011692 CrossRefPubMedPubMedCentral

Rund D (2016) Thalassemia 2016: modern medicine battles an ancient disease. Am J Hematol 91(1):15–21. https://doi.org/10.1002/ajh.24231 CrossRefPubMed

Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M (2018) Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med 378(16):1479–1493. https://doi.org/10.1056/NEJMoa1705342 CrossRefPubMed

Suragani RN, Cawley SM, Li R, Wallner S, Alexander MJ, Mulivor AW, Gardenghi S, Rivella S, Grinberg AV, Pearsall RS, Kumar R (2014) Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia. Blood 123(25):3864–3872. https://doi.org/10.1182/blood-2013-06-511238 CrossRefPubMedPubMedCentral

Ashley-Koch AE, Elliott L, Kail ME, De Castro LM, Jonassaint J, Jackson TL, Price J, Ataga KI, Levesque MC, Weinberg JB, Orringer EP, Collins A, Vance JM, Telen MJ (2008) Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease. Blood 111(12):5721–5726. https://doi.org/10.1182/blood-2007-02-074849 CrossRefPubMedPubMedCentral

Breda L, Rivella S (2014) Modulators of erythropoiesis: emerging therapies for hemoglobinopathies and disorders of red cell production. Hematol Oncol Clin North Am 28(2):375–386. https://doi.org/10.1016/j.hoc.2013.12.001 CrossRefPubMedPubMedCentral

Kajita T, Ariyoshi W, Okinaga T, Mitsugi S, Tominaga K, Nishihara T (2018) Mechanisms involved in enhancement of osteoclast formation by activin-A. J Cell Biochem 119(8):6974–6985. https://doi.org/10.1002/jcb.26906 CrossRefPubMed

Rosenberg N, Soudry M, Rosenberg O, Blumenfeld I, Blumenfeld Z (2010) The role of activin A in the human osteoblast cell cycle: a preliminary experimental in vitro study. Exp Clin Endocrinol Diabetes 118(10):708–712. https://doi.org/10.1055/s-0030-1249007 CrossRefPubMed

Alves RD, Eijken M, Bezstarosti K, Demmers JA, van Leeuwen JP (2013) Activin A suppresses osteoblast mineralization capacity by altering extracellular matrix (ECM) composition and impairing matrix vesicle (MV) production. Mol Cell Proteomics 12(10):2890–2900. https://doi.org/10.1074/mcp.M112.024927 CrossRefPubMedPubMedCentral

10.

Nicks KM, Perrien DS, Akel NS, Suva LJ, Gaddy D (2009) Regulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, activin and inhibin. Mol Cell Endocrinol 310(1–2):11–20. https://doi.org/10.1016/j.mce.2009.07.001 CrossRefPubMedPubMedCentral

11.

Arlet JB, Guillem F, Lamarque M, Dussiot M, Maciel T, Moura I, Hermine O, Courtois G (2016) Protein-based therapeutic for anemia caused by dyserythropoiesis. Expert Rev Proteomics 13:1–10. https://doi.org/10.1080/14789450.2016.1240622 CrossRef

12.

Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, Knight R, Srinivasan S, Terpos E (2014) Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol 165(6):814–823. https://doi.org/10.1111/bjh.12835 CrossRefPubMedPubMedCentral

13.

Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, Stamatoullas A, DeZern AE, Delaunay J, Borthakur G, Rifkin R, Boyd TE, Laadem A, Vo B, Zhang J, Puccio-Pick M, Attie KM, Fenaux P, List AF (2018) Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol 5(2):e63–e72. https://doi.org/10.1016/S2352-3026(18)30002-4 CrossRefPubMed

14.

Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A (2017) Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol 18(10):1338–1347. https://doi.org/10.1016/S1470-2045(17)30615-0 CrossRefPubMed

15.

Nguyen TV, Pocock N, Eisman JA (2000) Interpretation of bone mineral density measurement and its change. J Clin Densitom 3(2):107–119CrossRefPubMed

16.

Taher AT, Weatherall DJ, Cappellini MD (2018) Thalassaemia. Lancet 391(10116):155–167. https://doi.org/10.1016/S0140-6736(17)31822-6 CrossRefPubMed

17.

Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet 376(9757):2018–2031. https://doi.org/10.1016/S0140-6736(10)61029-X CrossRefPubMed

18.

Mylonas I, Schiessl B, Jeschke U, Vogl J, Makrigiannakis A, Kuhn C, Schulze S, Kainer F, Friese K (2006) Expression of inhibin/activin subunits alpha (-alpha), betaA (-betaA), and betaB (-betaB) in placental tissue of normal, preeclamptic, and HELLP pregnancies. Endocr Pathol 17(1):19–33CrossRefPubMed

19.

Dhaliwal G, Cornett PA, Tierney LM Jr (2004) Hemolytic anemia. Am Fam Physician 69(11):2599–2606PubMed

20.

Murata M, Onomichi K, Eto Y, Shibai H, Muramatsu M (1988) Expression of erythroid differentiation factor (EDF) in Chinese hamster ovary cells. Biochem Biophys Res Commun 151(1):230–235CrossRefPubMed

21.

Broxmeyer HE, Lu L, Cooper S, Schwall RH, Mason AJ, Nikolics K (1988) Selective and indirect modulation of human multipotential and erythroid hematopoietic progenitor cell proliferation by recombinant human activin and inhibin. Proc Natl Acad Sci U S A 85(23):9052–9056CrossRefPubMedPubMedCentral

22.

Pearson S, Sroczynska P, Lacaud G, Kouskoff V (2008) The stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF. Development 135(8):1525–1535. https://doi.org/10.1242/dev.011767 CrossRefPubMed

23.

Shav-Tal Y, Zipori D (2002) The role of activin a in regulation of hemopoiesis. Stem Cells 20(6):493–500. https://doi.org/10.1634/stemcells.20-6-493 CrossRefPubMed

24.

Maguer-Satta V, Bartholin L, Jeanpierre S, Gadoux M, Bertrand S, Martel S, Magaud JP, Rimokh R (2001) Expression of FLRG, a novel activin A ligand, is regulated by TGF-beta and during hematopoiesis [corrected]. Exp Hematol 29(3):301–308CrossRefPubMed

25.

Utsugisawa T, Moody JL, Aspling M, Nilsson E, Carlsson L, Karlsson S (2006) A road map toward defining the role of Smad signaling in hematopoietic stem cells. Stem Cells 24(4):1128–1136. https://doi.org/10.1634/stemcells.2005-0263 CrossRefPubMed

26.

Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, Eto Y (1992) Evidence for the participation of endogenous activin A/erythroid differentiation factor in the regulation of erythropoiesis. Proc Natl Acad Sci U S A 89(5):1553–1556CrossRefPubMedPubMedCentral

27.

Shiozaki M, Sakai R, Tabuchi M, Eto Y, Kosaka M, Shibai H (1989) In vivo treatment with erythroid differentiation factor (EDF/activin A) increases erythroid precursors (CFU-E and BFU-E) in mice. Biochem Biophys Res Commun 165(3):1155–1161CrossRefPubMed

28.

Maguer-Satta V, Bartholin L, Jeanpierre S, Ffrench M, Martel S, Magaud JP, Rimokh R (2003) Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFbeta family. Exp Cell Res 282(2):110–120CrossRefPubMed

29.

Yu J, Shao L, Vaughan J, Vale W, Yu AL (1989) Characterization of the potentiation effect of activin on human erythroid colony formation in vitro. Blood 73(4):952–960PubMed

30.

Mizuguchi T, Kosaka M, Saito S (1993) Activin A suppresses proliferation of interleukin-3-responsive granulocyte-macrophage colony-forming progenitors and stimulates proliferation and differentiation of interleukin-3-responsive erythroid burst-forming progenitors in the peripheral blood. Blood 81(11):2891–2897PubMed

31.

Nakao K, Kosaka M, Saito S (1991) Effects of erythroid differentiation factor (EDF) on proliferation and differentiation of human hematopoietic progenitors. Exp Hematol 19(11):1090–1095PubMed

32.

Eto Y, Tsuji T, Takezawa M, Takano S, Yokogawa Y, Shibai H (1987) Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1. Biochem Biophys Res Commun 142(3):1095–1103CrossRefPubMed

33.

Yu J, Shao LE, Lemas V, Yu AL, Vaughan J, Rivier J, Vale W (1987) Importance of FSH-releasing protein and inhibin in erythrodifferentiation. Nature 330(6150):765–767. https://doi.org/10.1038/330765a0 CrossRefPubMed

34.

Frigon NL Jr, Shao L, Young AL, Maderazo L, Yu J (1992) Regulation of globin gene expression in human K562 cells by recombinant activin A. Blood 79(3):765–772PubMed

35.

Schwall R, Schmelzer CH, Matsuyama E, Mason AJ (1989) Multiple actions of recombinant activin-A in vivo. Endocrinology 125(3):1420–1423. https://doi.org/10.1210/endo-125-3-1420 CrossRefPubMed

36.

Broxmeyer HE, Hangoc G, Zucali JR, Mason A, Schwall R, Carow C, Cooper S (1991) Effects in vivo of purified recombinant human activin and erythropoietin in mice. Int J Hematol 54(6):447–454PubMed

37.

Soderberg SS, Karlsson G, Karlsson S (2009) Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling. Ann N Y Acad Sci 1176:55–69. https://doi.org/10.1111/j.1749-6632.2009.04569.x CrossRefPubMed

38.

Anastasilakis AD, Polyzos SA, Makras P, Gkiomisi A, Savvides M, Papatheodorou A, Terpos E (2013) Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment. Osteoporos Int 24(7):2127–2132. https://doi.org/10.1007/s00198-012-2198-0 CrossRefPubMed

39.

Terpos E, Kastritis E, Christoulas D, Gkotzamanidou M, Eleutherakis-Papaiakovou E, Kanellias N, Papatheodorou A, Dimopoulos MA (2012) Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy. Ann Oncol 23(10):2681–2686. https://doi.org/10.1093/annonc/mds068 CrossRefPubMed

40.

Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, Santo L, Cirstea D, Patel K, Sohani AR, Guimaraes A, Xie W, Chauhan D, Schoonmaker JA, Attar E, Churchill M, Weller E, Munshi N, Seehra JS, Weissleder R, Anderson KC, Scadden DT, Raje N (2010) Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci U S A 107(11):5124–5129. https://doi.org/10.1073/pnas.0911929107 CrossRefPubMedPubMedCentral

41.

Leto G, Incorvaia L, Badalamenti G, Tumminello FM, Gebbia N, Flandina C, Crescimanno M, Rini G (2006) Activin A circulating levels in patients with bone metastasis from breast or prostate cancer. Clin Exp Metastasis 23(2):117–122. https://doi.org/10.1007/s10585-006-9010-5 CrossRefPubMed

42.

Piga A (2017) Impact of bone disease and pain in thalassemia. Hematology Am Soc Hematol Educ Program 2017(1):272–277. https://doi.org/10.1182/asheducation-2017.1.272 CrossRefPubMedPubMedCentral

43.

Ikenoue T, Jingushi S, Urabe K, Okazaki K, Iwamoto Y (1999) Inhibitory effects of activin-A on osteoblast differentiation during cultures of fetal rat calvarial cells. J Cell Biochem 75(2):206–214CrossRefPubMed

44.

Loots GG, Keller H, Leupin O, Murugesh D, Collette NM, Genetos DC (2012) TGF-beta regulates sclerostin expression via the ECR5 enhancer. Bone 50(3):663–669. https://doi.org/10.1016/j.bone.2011.11.016 CrossRefPubMed

45.

Voskaridou E, Christoulas D, Plata E, Bratengeier C, Anastasilakis AD, Komninaka V, Kaliontzi D, Gkotzamanidou M, Polyzos SA, Dimopoulou M, Terpos E (2012) High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density. Horm Metab Res 44(12):909–913. https://doi.org/10.1055/s-0032-1312618 CrossRefPubMed

46.

Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang Y, Condon CH, Sherman ML (2009) Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res 24(4):744–752. https://doi.org/10.1359/jbmr.081208 CrossRefPubMed

47.

Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, Grapton D, Paubelle E, Payen E, Beuzard Y, Leboulch P, Ribeil JA, Arlet JB, Cote F, Courtois G, Ginzburg YZ, Daniel TO, Chopra R, Sung V, Hermine O, Moura IC (2014) An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med 20(4):398–407. https://doi.org/10.1038/nm.3468 CrossRefPubMed

48.

Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, Raymon HK, Heise C, Daniel T, Chopra R, Sung V (2014) An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol 165(6):870–882. https://doi.org/10.1111/bjh.12838 CrossRefPubMedPubMedCentral

49.

Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V, Hoffman R (2013) Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol 41(2):155–166 e117. https://doi.org/10.1016/j.exphem.2012.12.002 CrossRefPubMed

50.

Flotta S, Delbini P, Graziadei G, Marcon A, Sung V, Cappellini MD (2015) Erythropoietic response to a ligand trap of activin receptor II in cultures from β-thalassemia patients. EHA Learning Center. Flotta S. 102769

51.

Langdon JM, Barkataki S, Berger AE, Cheadle C, Xue QL, Sung V, Roy CN (2015) RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice. Am J Hematol 90(1):8–14. https://doi.org/10.1002/ajh.23856 CrossRefPubMed

52.

Malek M, Heise C, Chopra R, Daniel TO, Sung V (2013) Sotatercept, an activin receptor-2a ligand trap, modulates hepcidin levels in primary human hepatocytes. Blood 122:3441

53.

Cappellini MD, Porter J, Origa R, Forni GL, Voskaridou E, Taher AT, Laadem A, Galactéros F, Miteva D, Sung V, Chopra R, Arlet J-B, Ribeil J-A, Zou J, Chen N, Attie KM, Garbowski M, Graziadei G, Balocco M, Hermine O (2015) Interim results from a phase 2a, open-label, dose-finding study of sotatercept (ACE-011) in adult patients (pts) with beta-thalassemia. EHA Learning Center. Domenica Cappellini M. 103081

54.

Oikonomidou P, La P, Gupta R, Presti V, Casu C, Breda L, Watson D, Suragani R, Kumar R, Rivella S (2016) Genetic investigation of the role of GDF11 in the treatment of β-thalassemia and MDS. Blood 128:2439

55.

Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, Alexander MJ, Devine M, Loveday KS, Underwood KW, Grinberg AV, Quisel JD, Chopra R, Pearsall RS, Seehra J, Kumar R (2014) Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 20(4):408–414. https://doi.org/10.1038/nm.3512 CrossRefPubMed

56.

Martinez PA, Suragani RN, Bhasin M, Li R, Pearsall RS, Kumar R (2015) Rap-536 (murine ACE-536/luspatercept) inhibits Smad2/3 signaling and promotes erythroid differentiation by restoring GATA-1 function in murine b-thalassemia. Blood 126:751

57.

Piga A, Tartaglione I, Gamberini MR, Voskaridou E, Melpignano A, Ricchi P, Caruso V, Pietrangelo A, Reynolds J, Barron C, Zhang X, Laadem A, Linde PG, Sherman ML (2018) Improvements in hemoglobin, quality of life, and six-minute-walk distance in adults with b-thalassemia treated with luspatercept: long-term phase 2 study. EHA Learning Center. Piga A. 214458

58.

Chen N, Laadem A, Wilson DM, Zhang X, Sherman ML, Ritland S, Attie KM (2016) Pharmacokinetics and exposure-response of luspatercept in patients with beta-thalassemia: preliminary results from phase 2 studies. Blood 128:2463CrossRef

59.

Piga A, Perrotta S, Melpignano A, Borgna-Pignatti C, Gamberini MR, Voskaridou E, Caruso V, Ricchi P, Pietrangelo A, Zhang X, Wilson D, Bellevue A, Laadem A, Sherman M, Attie K (2016) Luspatercept decreases transfusion burden and liver iron concentration in regularly transfused adults with beta-thalassemia. EHA Learning Center. Piga A. 135330

Titel: Activin-A is elevated in patients with thalassemia major and double heterozygous sickle cell/beta-thalassemia and correlates with markers of hemolysis and bone mineral density
verfasst von: Ersi Voskaridou
Ioannis Ntanasis-Stathopoulos
Dimitrios Christoulas
Maria Dimopoulou
Veroniki Komninaka
Konstantina Repa
Athanasios Papatheodorou
Evangelos Terpos
Publikationsdatum: 30.04.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology / Ausgabe 7/2019
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-019-03695-x

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Activin-A is elevated in patients with thalassemia major and double heterozygous sickle cell/beta-thalassemia and correlates with markers of hemolysis and bone mineral density

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