Follistatin Effects in Migration, Vascularization, and Osteogenesis in vitro and Bone Repair in vivo
Shorouk Fahmy-Garcia, Eric Farrell, Janneke Witte-Bouma, Iris Robbesom-van den Berge, Melva Suarez, Didem Mumcuoglu, Heike Walles, Sebastiaan G J M Kluijtmans, Bram C J van der Eerden, Gerjo J V M van Osch, Johannes P T M van Leeuwen, Marjolein van Driel, Shorouk Fahmy-Garcia, Eric Farrell, Janneke Witte-Bouma, Iris Robbesom-van den Berge, Melva Suarez, Didem Mumcuoglu, Heike Walles, Sebastiaan G J M Kluijtmans, Bram C J van der Eerden, Gerjo J V M van Osch, Johannes P T M van Leeuwen, Marjolein van Driel
Abstract
The use of biomaterials and signaling molecules to induce bone formation is a promising approach in the field of bone tissue engineering. Follistatin (FST) is a glycoprotein able to bind irreversibly to activin A, a protein that has been reported to inhibit bone formation. We investigated the effect of FST in critical processes for bone repair, such as cell recruitment, osteogenesis and vascularization, and ultimately its use for bone tissue engineering. In vitro, FST promoted mesenchymal stem cell (MSC) and endothelial cell (EC) migration as well as essential steps in the formation and expansion of the vasculature such as EC tube-formation and sprouting. FST did not enhance osteogenic differentiation of MSCs, but increased committed osteoblast mineralization. In vivo, FST was loaded in an in situ gelling formulation made by alginate and recombinant collagen-based peptide microspheres and implanted in a rat calvarial defect model. Two FST variants (FST288 and FST315) with major differences in their affinity to cell-surface proteoglycans, which may influence their effect upon in vivo bone repair, were tested. In vitro, most of the loaded FST315 was released over 4 weeks, contrary to FST288, which was mostly retained in the biomaterial. However, none of the FST variants improved in vivo bone healing compared to control. These results demonstrate that FST enhances crucial processes needed for bone repair. Further studies need to investigate the optimal FST carrier for bone regeneration.
Keywords: bone tissue engineering; follistatin 288 (FST288); follistatin 315 (FST315); injectable in situ gelling slow release system; migration; osteogenesis; regenerative medicine; vascularization.
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References
- Abe Y., Abe T., Aida Y., Hara Y., Maeda K. (2004a). Follistatin restricts bone morphogenetic protein (BMP)-2 action on the differentiation of osteoblasts in fetal rat mandibular cells. J. Bone Miner. Res. 19, 1302–1307. 10.1359/JBMR.040408
- Abe Y., Minegishi T., Leung P. C. (2004b). Activin receptor signaling. Growth Factors 22, 105–110. 10.1080/08977190410001704688
- Alves R. D., Eijken M., Bezstarosti K., Demmers J. A., van Leeuwen J. P. (2013). Activin A suppresses osteoblast mineralization capacity by altering extracellular matrix (ECM) composition and impairing matrix vesicle (MV) production. Mol. Cell Proteomics 12, 2890–2900. 10.1074/mcp.M112.024927
- Barakat B., O'Connor A. E., Gold E., de Kretser D. M., Loveland K. L. (2008). Inhibin, activin, follistatin and FSH serum levels and testicular production are highly modulated during the first spermatogenic wave in mice. Reproduction 136, 345–359. 10.1530/REP-08-0140
- Bialek P., Parkington J., Li X., Gavin D., Wallace C., Zhang J., et al. . (2014). A myostatin and activin decoy receptor enhances bone formation in mice. Bone 60, 162–171. 10.1016/j.bone.2013.12.002
- Bowser M., Herberg S., Arounleut P., Shi X., Fulzele S., Hill W. D., et al. . (2013). Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp. Gerontol. 48, 290–297. 10.1016/j.exger.2012.11.004
- Cash J. N., Angerman E. B., Keutmann H. T., Thompson T. B. (2012). Characterization of follistatin-type domains and their contribution to myostatin and activin A antagonism. Mol. Endocrinol. 26, 1167–1178. 10.1210/me.2012-1061
- Chiba H., Sawada N., Ono T., Ishii S., Mori M. (1993). Establishment and characterization of a simian virus 40-immortalized osteoblastic cell line from normal human bone. Jpn J. Cancer Res. 84, 290–297. 10.1111/j.1349-7006.1993.tb02869.x
- Datta-Mannan A., Yaden B., Krishnan V., Jones B. E., Croy J. E. (2013). An engineered human follistatin variant: insights into the pharmacokinetic and pharmocodynamic relationships of a novel molecule with broad therapeutic potential. J. Pharmacol. Exp. Ther. 344, 616–623. 10.1124/jpet.112.201491
- Eijken M., Koedam M., van Driel M., Buurman C. J., Pols H. A., van Leeuwen J. P. (2006). The essential role of glucocorticoids for proper human osteoblast differentiation and matrix mineralization. Mol. Cell. Endocrinol. 248, 87–93. 10.1016/j.mce.2005.11.034
- Eijken M., Swagemakers S., Koedam M., Steenbergen C., Derkx P., Uitterlinden A. G., et al. . (2007). The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J. 21, 2949–2960. 10.1096/fj.07-8080com
- Endo D., Kogure K., Hasegawa Y., Maku-uchi M., Kojima I. (2004). Activin A augments vascular endothelial growth factor activity in promoting branching tubulogenesis in hepatic sinusoidal endothelial cells. J. Hepatol. 40, 399–404. 10.1016/j.jhep.2003.11.019
- Fahmy-Garcia S., et al. (2017). Nell-1, HMGB1 and CCN2 enhance migration and vasculogenesis, but not osteogenic differentiation compared to BMP2. Tissue Eng Part A. 24, 207–218. 10.1089/ten.TEA.2016.0537
- Fajardo R. J., Manoharan R. K., Pearsall R. S., Davies M. V., Marvell T., Monnell T. E., et al. . (2010). Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis). Bone 46, 64–71. 10.1016/j.bone.2009.09.018
- Funaba M., Ogawa K., Murata T., Fujimura H., Murata E., Abe M., et al. . (1996). Follistatin and activin in bone: expression and localization during endochondral bone development. Endocrinology 137, 4250–4259. 10.1210/endo.137.10.8828484
- Gajos-Michniewicz A., Pawlowska E., Ochedalski T., Piastowska-Ciesielska A. (2012). The influence of follistatin on mechanical properties of bone tissue in growing mice with overexpression of follistatin. J. Bone Miner. Metab. 30, 426–433. 10.1007/s00774-011-0347-8
- Gajos-Michniewicz A., Piastowska A. W., Russell J. A., Ochedalski T. (2010). Follistatin as a potent regulator of bone metabolism. Biomarkers 15, 563–574. 10.3109/1354750X.2010.495786
- Gao X., Hu H., Zhu J., Xu Z. (2007). Identification and characterization of follistatin as a novel angiogenin-binding protein. FEBS Lett. 581, 5505–5510. 10.1016/j.febslet.2007.10.059
- Glienke J., Schmitt A. O., Pilarsky C., Hinzmann B., Weiss B., Rosenthal A., et al. . (2000). Differential gene expression by endothelial cells in distinct angiogenic states. Eur. J. Biochem. 267, 2820–2830. 10.1046/j.1432-1327.2000.01325.x
- Glister C., Kemp C. F., Knight P. G., Glister C., Kemp C. F., Knight P. G. (2004). Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4,−6 and−7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin. Reproduction 127, 239–254. 10.1530/rep.1.00090
- Gruber H. E., Gruber H. E. (1992). Adaptations of Goldner's Masson trichrome stain for the study of undecalcified plastic embedded bone. Biotech. Histochem. 67, 30–34. 10.3109/10520299209110002
- Hashimoto O., Kawasaki N., Tsuchida K., Shimasaki S., Hayakawa T., Sugino H. (2000). Difference between follistatin isoforms in the inhibition of activin signalling: activin neutralizing activity of follistatin isoforms is dependent on their affinity for activin. Cell. Signal. 12, 565–571. 10.1016/S0898-6568(00)00099-1
- Hedger M. p., Winnall W. R, Phillips D. J., de Kretser D. M. (2011). The regulation and functions of activin and follistatin in inflammation and immunity. Vitam. Horm. 85, 255–297. 10.1016/B978-0-12-385961-7.00013-5
- Hinck A. P., Huang T. (2013). TGF-beta antagonists: same knot, but different hold. Structure 21, 1269–1270. 10.1016/j.str.2013.07.015
- Inoue S., Nomura S., Hosoi T., Ouchi Y., Orimo H., Muramatsu M. (1994). Localization of follistatin, an activin-binding protein, in bone tissues. Calcif. Tissue Int. 55, 395–397. 10.1007/BF00299321
- Kawao N., Morita H., Obata K., Tatsumi K., Kaji H. (2017). Role of follistatin in muscle and bone alterations induced by gravity change in mice. J. Cell Physiol. 233, 1191–1201. 10.1002/jcp.25986
- Kirsch T., Nickel J., Sebald W. (2000). Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2. FEBS Lett. 468, 215–219. 10.1016/S0014-5793(00)01214-X
- Kleinhans C., Barz J., Wurster S., Willig M., Oehr C., Müller M., et al. . (2013). Ammonia plasma treatment of polystyrene surfaces enhances proliferation of primary human mesenchymal stem cells and human endothelial cells. Biotechnol. J. 8, 327–337. 10.1002/biot.201200210
- Koseki T., Gao Y., Okahashi N., Murase Y., Tsujisawa T., Sato T., et al. . (2002). Role of TGF-beta family in osteoclastogenesis induced by RANKL. Cell Signal. 14, 31–36. 10.1016/S0898-6568(01)00221-2
- Kozian D. H., Augustin H. G., Kozian D. H., Augustin H. G. (1995). Rapid identification of differentially expressed endothelial cell genes by RNA display. Biochem. Biophys. Res. Commun. 209, 1068–1075. 10.1006/bbrc.1995.1606
- Kozian D. H., Ziche M., Augustin H. G., Kozian D. H., Ziche M. (1997). The activin-binding protein follistatin regulates autocrine endothelial cell activity and induces angiogenesis. Lab. Invest. 76, 267–276.
- Kretlow J. D., Young S., Klouda L., Wong M., Mikos A. G. (2009). Injectable biomaterials for regenerating complex craniofacial tissues. Adv. Mater. 21, 3368–3393. 10.1002/adma.200802009
- Krneta J., Kroll J., Alves F., Prahst C., Sananbenesi F., Dullin C., et al. . (2006). Dissociation of angiogenesis and tumorigenesis in follistatin- and activin-expressing tumors. Cancer Res. 66, 5686–5695. 10.1158/0008-5472.CAN-05-3821
- Lowry O. H., Roberts N. R, Wu M. L, Hixon W. S, Crawford E. J., et al. . (1954). The quantitative histochemistry of brain. II. Enzyme measurements. J. Biol. Chem. 207, 19–37.
- Maeshima A., Mishima K., Yamashita S., Nakasatomi M., Miya M., Sakurai N., et al. . (2014). Follistatin, an activin antagonist, ameliorates renal interstitial fibrosis in a rat model of unilateral ureteral obstruction. Biomed. Res Int. 2014:376191. 10.1155/2014/376191
- Maeshima K., Maeshima A., Hayashi Y., Kishi S., Kojima I. (2004). Crucial role of activin a in tubulogenesis of endothelial cells induced by vascular endothelial growth factor. Endocrinology 145, 3739–3745. 10.1210/en.2004-0213
- Matzuk M. M., Lu N., Vogel H., Sellheyer K., Roop D. R., Bradley A. (1995). Multiple defects and perinatal death in mice deficient in follistatin. Nature 374, 360–363. 10.1038/374360a0
- Mumcuoglu D., de Miguel L., Jekhmane S., Siverino C., Nickel J., Mueller T. D., et al. . (2017). Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2. Mater. Sci. Eng. C 84, 271–280. 10.1016/j.msec.2017.11.031
- Mumcuoglu D., Fahmy-Garcia S., Ridwan Y., Nicke J., Farrell E., Kluijtmans S. G., et al. . (2018). Injectable BMP-2 delivery system based on collagen-derived microspheres and alginate induced bone formation in a time- and dose-dependent manner. Eur. Cell Mater. 35, 242–254. 10.22203/eCM.v035a17
- Nagamine T., Imamura T., Ishidou Y., Kato M., Murata F., ten Dijke P., et al. . (1998). Immunohistochemical detection of activin A, follistatin, and activin receptors during fracture healing in the rat. J. Orthop. Res. 16, 314–321. 10.1002/jor.1100160307
- Nakamura T., Sugino K., Titani K., Sugino H. (1991). Follistatin, an activin-binding protein, associates with heparan sulfate chains of proteoglycans on follicular granulosa cells. J. Biol. Chem. 266, 19432–19437.
- Ogino H., Yano S., Kakiuchi S., Muguruma H., Ikuta K., Hanibuchi M., et al. . (2008). Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice. Clin. Cancer Res. 14, 660–667. 10.1158/1078-0432.CCR-07-1221
- Patel K. (1998). Follistatin. Int. J. Biochem. Cell Biol. 30, 1087–1093. 10.1016/S1357-2725(98)00064-8
- Pearsall R. S., Canalis E., Cornwall-Brady M., Underwood K. W., Haigis B., Ucran J., et al. . (2008). A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc. Natl. Acad. Sci. U. S. A. 105, 7082–7087. 10.1073/pnas.0711263105
- Phillips D. J. (1998). de Kretser, Follistatin: a multifunctional regulatory protein. Front. Neuroendocrinol. 19, 287–322. 10.1006/frne.1998.0169
- Poon B., Kha T., Tran S., Dass C. R. (2016). Bone morphogenetic protein-2 and bone therapy: successes and pitfalls. J. Pharm. Pharmacol. 68, 139–147. 10.1111/jphp.12506
- Rahman M. S., Akhtar N., Jamil H. M., Banik R. S., Asaduzzaman S. M. (2015). TGF-beta/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3:15005. 10.1038/boneres.2015.5
- Sakai R., Eto Y., Ohtsuka M., Hirafuji M., Shinoda H. (1993). Activin enhances osteoclast-like cell formation in vitro. Biochem. Biophys. Res. Commun. 195, 39–46. 10.1006/bbrc.1993.2006
- Schneyer A., Schoen A., Quigg A., Sidis Y. (2003). Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG). Endocrinology 144, 1671–1674. 10.1210/en.2002-0203
- Schneyer A. L., Wang Q., Sidis Y., Sluss P. M. (2004). Differential distribution of follistatin isoforms: application of a new FS315-specific immunoassay. J. Clin. Endocrinol. Metab. 89, 5067–5075. 10.1210/jc.2004-0162
- Sidis Y., Mukherjee A., Keutmann H., Delbaere A., Sadatsuki M., Schneyer A. (2006). Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins. Endocrinology 147, 3586–3597. 10.1210/en.2006-0089
- Sidis Y., Schneyer A. L., Sluss P. M., Johnson L. N., Keutmann H. T. (2001). Follistatin: essential role for the N-terminal domain in activin binding and neutralization. J. Biol. Chem. 276, 17718–17726. 10.1074/jbc.M100736200
- Spicer P. P., Kretlow J. D., Young S., Jansen J. A., Kasper F. K., Mikos A. G. (2012). Evaluation of bone regeneration using the rat critical size calvarial defect. Nat. Protoc. 7, 1918–1929. 10.1038/nprot.2012.113
- Thompson T. B., Lerch T. F., Cook R. W., Woodruff T. K., Jardetzky T. S. (2005). The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev. Cell. 9, 535–543. 10.1016/j.devcel.2005.09.008
- Venkatesan J., Jenkatesana J., Bhatnagar I., Manivasagan P., Kang K-W., Kim S-K., et al. . (2015). Alginate composites for bone tissue engineering: a review. Int. J. Biol. Macromol. 72, 269–281. 10.1016/j.ijbiomac.2014.07.008
- Wennberg C., Hessle L., Lundberg P., Mauro S., Narisawa S., Lerner U. H., et al. . (2000). Functional characterization of osteoblasts and osteoclasts from alkaline phosphatase knockout mice. J. Bone Miner. Res. 15, 1879–1888. 10.1359/jbmr.2000.15.10.1879
- Wu M., Chen G., Li Y. P., Wu M., Chen G., Li Y. P. (2016). TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4:16009. 10.1038/boneres.2016.9
- Yaden B. C., Croy J. E., Wang Y., Wilson J. M., Datta-Mannan A., Shetler P., et al. . (2014). Follistatin: a novel therapeutic for the improvement of muscle regeneration. J. Pharmacol. Exp. Ther. 349, 355–371. 10.1124/jpet.113.211169
- Zhu J., Li Y., Lu A., Gharaibeh B., Ma J., Kobayashi T., et al. . (2011). Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis. Am. J. Pathol. 179, 915–930. 10.1016/j.ajpath.2011.04.008
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