Activin-Antagonisten in der Therapie der Osteoporose

Zusammenfassung

Activin A ist ein Polypeptid mit vielfältigen biologischen Wirkungen auf die Regulation der Fertilität, die Pluripotenz und Differenzierung von Stammzellen, die Differenzierung von Neuronen, Inselzellen und Immunzellen und die Regulation des Stoffwechsels. Activin gehört zu den Liganden der Familie der TGFβ- Superfamilie. Die Activine A, B und C binden an die Typ-II-BMP-Rezeptoren (Activin-Rezeptor IIA [ActRIIA] und IIB [ActRIIB]) und rekrutieren spezifische Typ-I-Rezeptoren (activin receptor-like kinase 2 [ALK2], 4 [ALK4] und 7 ]ALK7]). Da der ActRIIB auch andere Faktoren wie z. B. Myostatin (GDF8) und die Bone Morphogenetic Proteins 7 und 2 (BMP-7, BMP-2) bindet, konkurrieren diese Liganden um den Rezeptor. Im Alter findet man erhöhte Activin- Spiegel im Serum. Activin-Antagonisten verändern die Balance zwischen den verschiedenen Liganden und verursachen eine veränderte Genregulation an allen Zellen, die entsprechende Signalsysteme exprimieren. Ein ACTIIIGG- Fusionsprotein mit Activin-antagonistischer Wirkung wird unter dem Namen Sotatercept (ACE-011) bereits klinisch als Medikament gegen die Tumor-induzierte und die Chemotherapie- induzierte Anämie erprobt und präklinisch für die Therapie der Osteoporose entwickelt. Am Knochen entfaltet der Antagonist eine duale Wirkung, er zeigt ausgeprägte anabole Effekte und verringert die Knochenresorption. In einem Mausmodell der Androgendefizienz werden zudem eine anabole Wirkung am Muskel und eine Verringerung des Fettgewebes beschrieben. Weitere Studien sind auf dem Weg, um sicherzustellen, dass das vielversprechende Medikament bei der Anwendung am Menschen neben der Effizienz auch ein gutes Sicherheits- und Nebenwirkungsprofil besitzt. Wenn es die Klinikreife erreicht, wird es unser therapeutisches Arsenal zur Behandlung der Osteoporose und möglicherweise auch der Sarkopenie wesentlich bereichern.

Summary

Activin A is a polypeptide displaying a diversity of biological effects such as regulation of fertility, pluripotency and differentiation of stem cells, differentiation of neuronal cells, pancreatic islet cells, immune cells and regulation of metabolism. Activins belong to the TGFβ superfamily of ligands. Activin A, B and C bind to specific type II receptors (activin-receptors IIA [ActRIIA] and IIB [ActRIIB]) thereby recruiting specific type I receptors (activin receptorlike kinase 2 [ALK2], 4 [ALK4] and 7 [ALK7]). ActRIIB may also bind other factors like myostatin (GDF8) and the bone morphogenetic proteins 7 and 2 (BMP-7, BMP-2), hence these ligands compete for the binding sites. Serum activin levels are elevated in the elderly. Activin antagonists modify the balance between the diversity of ligands thereby changing gene expression in tissues responsive to the respective signal transduction systems. An ACTII-IGG fusion protein, Sotatercept (ACE-011), displaying activin ant agonistic efficacy, is already clinically developed as a treatment for tumor- and chemotherapy-associated anemia and is also in preclinical development for the treatment of osteoporosis. This antagonist exerts dual effects in bone in that it displays both strong anabolic efficacy combined with antiresorptive effects. Moreover, in a mouse model of androgen deficiency marked muscle anabolic effects have been demonstrated as well as a reduction of adipose tissue. Future studies will have to show that its profile of safety and side effects allows applications in the human setting. If it will reach the clinical stage it will represent a promising additional strategy to treat osteoporosis and sarcopenia in the elderly.

Schlüsselwörter

Osteoporose - Activin - Activin-Antagonisten - TGFβ-Superfamilie

Keywords

Osteoporosis - Activin - Activin antagonists - TGFβ superfamily

• Literatur

• 1 Ageta H, Tsuchida K. Multifunctional roles of activins in the brain. Vitam Horm 2011; 85: 185-206.
• 2 Aleman-Muench GR, Soldevila G. When versatility matters: activins/inhibins as key regulators of immunity. Immunol Cell Biol. 2011 May 3. [Epub ahead of print].
• 3 Baccarelli A, Morpurgo PS, Corsi A. et al. Activin A serum levels and aging of the pituitary-gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects. Exp Gerontol 2001; 36: 1403-1412.
• 4 Beattie GM, Lopez AD, Bucay N. et al. Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cells 2005; 23: 489-495.
• 5 Bellinge RH, Liberles DA, Iaschi SP. et al. Myostatin and its implications on animal breeding: a review. Anim Genet 2005; 36: 1-6.
• 6 Centrella M, McCarthy TL, Canalis E. Activin-A binding and biochemical effects in osteoblast-enriched cultures from fetal-rat parietal bone. Mol Cell Biol 1991; 11: 250-258.
• 7 Chen YG, Wang Q, Lin SL. et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis. Exp Biol Med (Maywood) 2006; 231: 534-544.
• 8 Coss D, Mellon PL, Thackray VG. A FoxL in the Smad house: activin regulation of FSH. Trends Endocrinol Metab 2010; 21: 562-568.
• 9 Djouad F, Jackson WM, Bobick BE. et al. Activin A expression regulates multipotency of mesenchymal progenitor cells. Stem Cell Res Ther 2010; 01: 11.
• 10 Eijken M, Swagemakers S, Koedam M. et al. The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J 2007; 21: 2949-2960.
• 11 Fajardo RJ, Manoharan RK, Pearsall RS. et al. 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 2010; 46: 64-71.
• 12 Gaddy-Kurten D, Coker JK, Abe E. et al. Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 2002; 143: 74-83.
• 13 Han S. Crystal structure of activin receptor type IIB kinase domain. Vitam Horm 2011; 85: 29-38.
• 14 Hashimoto M, Shoda A, Inoue S. et al. Functional regulation of osteoblastic cells by the interaction of activin-A with follistatin. J Biol Chem 1992; 267: 4999-5004.
• 15 Ikenoue T, Jingushi S, Urabe K. et al. Inhibitory effects of activin-A on osteoblast differentiation during cultures of fetal rat calvarial cells. J Cell Biochem 1999; 75: 206-214.
• 16 Kelber JA, Shani G, Booker EC. et al. Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal. J Biol Chem 2008; 283: 4490-4500.
• 17 Klein NA, Houmard BS, Hansen KR. et al. Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab 2004; 89: 2977-2981.
• 18 Koncarevic A, Cornwall-Brady M, Pullen A. et al. A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health. Endocrinology 2010; 151: 4289-4300.
• 19 Lee SJ. Quadrupling muscle mass in mice by targeting TGF-beta signaling pathways. PLoS One 2007; 02: e789.
• 20 Lotinun S, Pearsall RS, Davies MV. et al. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone 2010; 46: 1082-1088.
• 21 Luo J, Tang M, Huang J. et al. TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells. J Biol Chem 2010; 285: 29588-29598.
• 22 Mathews LS. Activin receptors and cellular signaling by the receptor serine kinase family. Endocr Rev 1994; 15: 310-325.
• 23 Matzuk MM, Lu N, Vogel H. et al. Multiple defects and perinatal death in mice deficient in follistatin. Nature 1995; 374: 360-363.
• 24 Medeiros EF, Phelps MP, Fuentes FD, Bradley TM. Overexpression of follistatin in trout stimulates increased muscling. Am J Physiol Regul Integr Comp Physiol 2009; 297: R235-R242.
• 25 Nakamura T, Takio K, Eto Y. et al. Activin-binding protein from rat ovary is follistatin. Science 1990; 247: 836-838.
• 26 Oue Y, Kanatani H, Kiyoki M. et al. Effect of local injection of activin A on bone formation in newborn rats. Bone 1994; 15: 361-366.
• 27 Pangas SA, Woodruff TK. Activin signal transduction pathways. Trends Endocrinol Metab 2000; 11: 309-314.
• 28 Raje N, Vallet S. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Curr Opin Mol Ther 2010; 12: 586-597.
• 29 Ruckle J, Jacobs M, Kramer W. et al. Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res 2009; 24: 744-752.
• 30 Sakai R, Fujita S, Horie T. et al. Activin increases bone mass and mechanical strength of lumbar vertebrae in aged ovariectomized rats. Bone 2000; 27: 91-96.
• 31 Sakai R, Miwa K, Eto Y. Local administration of activin promotes fracture healing in the rat fibula fracture model. Bone 1999; 25: 191-196.
• 32 Sako D, Grinberg AV, Liu J. et al. Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb. J Biol Chem 2010; 285: 21037-21048.
• 33 Saremi A, Gharakhanloo R, Sharghi S. et al. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol 2010; 317: 25-30.
• 34 Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 2010; 06: 518-527.
• 35 Sugatani T, Alvarez UM, Hruska KA. Activin A stimulates IkappaB-alpha/NFkappaB and RANK expression for osteoclast differentiation, but not AKT survival pathway in osteoclast precursors. J Cell Biochem 2003; 90: 59-67.
• 36 Suresh PS, Rajan T, Tsutsumi R. (2011). New targets for old hormones: inhibins clinical role revisited. Endocr J 2011; 58: 223-235.
• 37 ten Dijke P, Miyazono K, Heldin CH. Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends Biochem Sci 2000; 25: 64-70.
• 38 Tsai ZY, Singh S, Yu SL. et al. Identification of microRNAs regulated by activin A in human embryonic stem cells. J Cell Biochem 2010; 109: 93-102.
• 39 Tsuchida K, Nakatani M, Uezumi A. et al. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J 2008; 55: 11-21.
• 40 van Dinther M, Visser N, de Gorter DJ. et al. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res 2010; 25: 1208-1215.
• 41 Xia Y, Schneyer AL. (2009). The biology of activin: recent advances in structure, regulation and function. J Endocrinol 2009; 202: 1-12.
• 42 Zamani N, Brown CW. Emerging Roles for the Transforming Growth Factor-Young adult female Cynomolgus monkeys Superfamily in Regulating Adiposity and Energy Expenditure. Endocr Rev 2011; 32: 387-403.