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Orphanet Journal of Rare Diseases

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Open Access 01-12-2023 | Fibrodysplasia Ossificans Progressiva | Research

The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva

Authors: Zhengqin Ye, Siyi Wang, Chang Shan, Qi Zhu, Ying Xue, Keqin Zhang

Published in: Orphanet Journal of Rare Diseases | Issue 1/2023

Abstract

Background

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients.

Results

We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients.

Conclusions

There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.

Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva (FOP): a disorder of osteochondrogenesis. Bone. 2020;140: 115539.PubMedPubMedCentralCrossRef

Zhang W, Zhang K, Song L, Pang J, Ma H, Shore EM, Kaplan FS, Wang P. The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases. Bone. 2013;57(2):386–91.PubMedPubMedCentralCrossRef

Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Diseases. 2011;6(1):1–6.CrossRef

Baujat G, Choquet R, Bouee S, Jeanbat V, Courouve L, Ruel A, Michot C, Le Quan Sang KH, Lapidus D, Messiaen C, Landais P, Cormier-Daire V. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis. 2017;12(1):123.PubMedPubMedCentralCrossRef

Pignolo RJ, Hsiao EC, Baujat G, Lapidus D, Sherman A, Kaplan FS. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis. 2021;16(1):350.PubMedPubMedCentralCrossRef

She D, Zhang K. Fibrodysplasia ossificans progressiva in China. Bone. 2018;109:101–3.PubMedCrossRef

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–7.PubMedCrossRef

Kaplan FSMM, Baujat G, Brown M, Cali A, Cho TJ, Crowe C, De Cunto CL, Delai P, Diecidue RJ, Rocco MI, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao EC, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos JC, Scott C, Shore EM, Zasloff MA, Zhang KQ, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2021;2:1–127.

Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137.PubMedPubMedCentralCrossRef

10.

Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA. 2015;112(50):15438–43.PubMedPubMedCentralCrossRef

11.

Hino K, Horigome K, Nishio M, Komura S, Nagata S, Zhao C, Jin Y, Kawakami K, Yamada Y, Ohta A, Toguchida J, Ikeya M. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J Clin Invest. 2017;127(9):3339–52.PubMedPubMedCentralCrossRef

12.

Upadhyay J, Xie L, Huang L, Das N, Stewart RC, Lyon MC, Palmer K, Rajamani S, Graul C, Lobo M, Wellman TJ, Soares EJ, Silva MD, Hesterman J, Wang L, Wen X, Qian X, Nannuru K, Idone V, Murphy AJ, Economides AN, Hatsell SJ. The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin a-dependent. J Bone Miner Res. 2017;32(12):2489–99.PubMedCrossRef

13.

Micha D, Voermans E, Eekhoff MEW, van Essen HW, Zandieh-Doulabi B, Netelenbos C, Rustemeyer T, Sistermans EA, Pals G, Bravenboer N. Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease. Bone. 2016;84:169–80.PubMedCrossRef

14.

Wang X, Li F, Xie L, Crane J, Zhen G, Mishina Y, Deng R, Gao B, Chen H, Liu S, Yang P, Gao M, Tu M, Wang Y, Wan M, Fan C, Cao X. Inhibition of overactive TGF-beta attenuates progression of heterotopic ossification in mice. Nat Commun. 2018;9(1):551.PubMedPubMedCentralCrossRef

15.

Shafritz AB, Shore EM, Gannon FH, Zasloff MA, Taub R, Muenke M, Kaplan FS. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med. 1996;335(8):556–61.CrossRef

16.

Barruet E, Morales BM, Lwin W, White MP, Theodoris CV, Kim H, Urrutia A, Wong SA, Srivastava D, Hsiao EC. The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated SMAD1/5/8 signaling. Stem Cell Res Ther. 2016;7(1):115.PubMedPubMedCentralCrossRef

17.

Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone. 2018;109:218–24.PubMedCrossRef

18.

Lin H, Ying Y, Wang YY, Wang G, Jiang SS, Huang D, Luo L, Chen YG, Gerstenfeld LC, Luo Z. AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation. Biochim Biophys Acta Mol Cell Res. 2017;1864(12):2369–77.PubMedCrossRef

19.

Hildebrand L, Stange K, Deichsel A, Gossen M, Seemann P. The fibrodysplasia ossificans progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response. Cell Signal. 2017;29:23–30.PubMedCrossRef

20.

Miljkovic ND, Cooper GM, Marra KG. Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells. Osteoarthritis Cartilage. 2008;16(10):1121–30.PubMedCrossRef

21.

Vukicevic S, Grgurevic L, Erjavec I, Pecin M, Bordukalo-Niksic T, Stokovic N, Lipar M, Capak H, Maticic D, Windhager R, Sampath TK, Gupta M. Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits. J Tissue Eng Regen Med. 2020;14(1):147–59.PubMedCrossRef

22.

Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore EM. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014;32(5):1289–300.PubMedCrossRef

23.

Kitoh H. Clinical aspects and current therapeutic approaches for FOP. Biomedicines. 2020;8(9):325.PubMedPubMedCentralCrossRef

24.

Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650–6.PubMedCrossRef

25.

Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F, Reis FM. Activin A in mammalian physiology. Physiol Rev. 2019;99(1):739–80.PubMedCrossRef

26.

Wang X, Fischer G, Hyvonen M. Structure and activation of pro-Activin A. Nat Commun. 2016;7:12052.PubMedPubMedCentralCrossRef

27.

Yaden BC, Wang YX, Wilson JM, Culver AE, Milner A, Datta-Mannan A, Shetler P, Croy JE, Dai G, Krishnan V. Inhibition of Activin A ameliorates skeletal muscle injury and rescues contractile properties by inducing efficient remodeling in female mice. Am J Pathol. 2014;184(4):1152–66.PubMedCrossRef

28.

Zhou J, Tai G, Liu H, Ge J, Feng Y, Chen F, Yu F, Liu Z. Activin A down-regulates the phagocytosis of lipopolysaccharide-activated mouse peritoneal macrophages in vitro and in vivo. Cell Immunol. 2009;255(1–2):69–75.PubMedCrossRef

29.

Wang Y, Cui X, Tai G, Ge J, Li N, Chen F, Yu F, Liu Z. A critical role of Activin A in maturation of mouse peritoneal macrophages in vitro and in vivo. Cell Mol Immunol. 2009;6(5):387–92.PubMedPubMedCentralCrossRef

30.

Wietecha MS, Pensalfini M, Cangkrama M, Muller B, Jin J, Brinckmann J, Mazza E, Werner S. Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds. Nat Commun. 2020;11(1):2604.PubMedPubMedCentralCrossRef

31.

Gaedeke J, Boehler T, Budde K, Neumayer HH, Peters H. Glomerular activin A overexpression is linked to fibrosis in anti-Thy1 glomerulonephritis. Nephrol Dial Transp. 2005;20(2):319–28.CrossRef

32.

Jones KL, Brauman JN, Groome NP, de Kretser DM, Phillips DJ. Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin. Endocrinology. 2000;141(5):1905–8.PubMedCrossRef

33.

Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, Phillips DJ. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci USA. 2007;104(41):16239–44.PubMedPubMedCentralCrossRef

34.

Ge J, Wang Y, Feng Y, Liu H, Cui X, Chen F, Tai G, Liu Z. Direct effects of activin A on the activation of mouse macrophage RAW264.7 cells. Cell Mol Immunol. 2009;6(2):129–33.PubMedPubMedCentralCrossRef

35.

Funaba M, Murakami M, Ikeda T, Ogawa K, Tsuchida K, Sugino H. Identification of tocopherol-associated protein as an activin/TGF-beta-inducible gene in mast cells. Biochim Biophys Acta. 2006;1763(8):900–6.PubMedCrossRef

36.

Linko RHM, Pettilä V, Ruokonen E, Ala-Kokko T, Ludlow H, de Kretser DM. Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection. BMC Infect Dis. 2014;14:253.PubMedPubMedCentralCrossRef

37.

Zhang LL, Liu CT. Activin A is associated with asthma in underweight and overweight patients. Genet Mol Res. 2015;14(1):440–52.PubMedCrossRef

38.

Tsai YL, Chou RH, Kuo CS, Chang CC, Wu CH, Huang PH, Chen JW, Lin SJ. Circulating activin A is a surrogate for the incidence of diastolic dysfunction and heart failure in patients with preserved ejection fraction. Circ J. 2019;83(7):1514–9.PubMedCrossRef

39.

La Rosa SUS, Billo P, Facco C, Sessa F, Capella C. Immunohistochemical localization of alpha- and betaA-subunits of inhibin/activin in human normal endocrine cells and related tumors of the digestive system. Virchows Arch. 1999;434(1):29–36.PubMedCrossRef

40.

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F. Proteomics tissue-based map of the human proteome. Science. 2015;347(6220):1260419.PubMedCrossRef

41.

Tuuri TEM, Hildén K, Ritvos O. The tissue distribution of activin beta A- and beta B-subunit and follistatin messenger ribonucleic acids suggests multiple sites of action for the activin-follistatin system during human development. J Clin Endocrinol Metab. 1994;78(6):1521–4.PubMed

42.

Mundy CYL, Sinha S, Chung J, Rux D, Catheline SE, Koyama E, Qin L, Pacifici M. Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice. Sci Signal. 2021;14(669):eabd0536.PubMedCrossRef

43.

Gannon FHKFS, Olmsted E, Finkel GC, Zasloff MA, Shore E. Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva. Hum Pathol. 1997;28:339–43.PubMedCrossRef

Title: The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva
Authors: Zhengqin Ye
Siyi Wang
Chang Shan
Qi Zhu
Ying Xue
Keqin Zhang
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Fibrodysplasia Ossificans Progressiva
Published in: Orphanet Journal of Rare Diseases / Issue 1/2023
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-023-02708-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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