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Methods for Controlling Mineralization Of (19) & (11) EP 2 097 515 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 5/077 (2010.01) A61B 17/58 (2006.01) 08.08.2012 Bulletin 2012/32 (86) International application number: (21) Application number: 07834699.6 PCT/NL2007/050571 (22) Date of filing: 16.11.2007 (87) International publication number: WO 2008/060156 (22.05.2008 Gazette 2008/21) (54) METHODS FOR CONTROLLING MINERALIZATION OF EXTRACELLULAR MATRIX, THERAPEUTIC METHODS BASED THEREON AND MEDICAMENTS FOR USE THEREIN VERFAHREN ZUR STEUERUNG DER MINERALISIERUNG EXTRAZELLULÄRER MATRIX, DARAUF BERUHENDE THERAPIEVERFAHREN UND ARZNEIMITTEL ZUR VERWENDUNG DABEI PROCÉDÉS DE CONTRÔLE DE LA MINÉRALISATION DE LA MATRICE EXTRACELLULAIRE, PROCÉDÉS THÉRAPEUTIQUES BASÉS SUR CEUX-CI ET MÉDICAMENTS DESTINÉS À ÊTRE UTILISÉS DANS CEUX-CI (84) Designated Contracting States: • EIJKEN ET AL: "The essential role of AT BE BG CH CY CZ DE DK EE ES FI FR GB GR glucocorticoids for proper human osteoblast HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE differentiation and matrix mineralization" SI SK TR MOLECULAR AND CELLULAR ENDOCRINOLOGY, AMSTERDAM, NL, vol. 248, (30) Priority: 17.11.2006 PCT/NL2006/000576 no. 1-2, 27 March 2006 (2006-03-27), pages 87-93, XP005335805 ISSN: 0303-7207 (43) Date of publication of application: • SAKAI R ET AL: "Local administration of activin 09.09.2009 Bulletin 2009/37 promotesfracture healing in the rat fibula fracture model." BONE AUG 1999, vol. 25, no. 2, August (60) Divisional application: 1999 (1999-08), pages 191-196, XP002440169 12164294.6 / 2 479 261 ISSN: 8756-3282 • "23 Activin secreted from hepatocytes activates (73) Proprietor: Arcarios B.V. HSCS and plays a key role in liver fibrosis" 3015 GD Rotterdam (NL) JOURNAL OF HEPATOLOGY, MUNKSGAARD INTERNATIONAL PUBLISHERS, COPENHAGEN, (72) Inventors: DK, vol. 42, April 2005 (2005-04), page 11, • VAN LEEUWEN, Johannes Petrus Thomas Maria XP005059834 ISSN: 0168-8278 1185 HP Amstelveen (NL) • WERNER ET AL: "Roles of activin in tissue repair, • EIJKEN, Hermanus Johannes Marco fibrosis, and inflammatory disease" CYTOKINE 3035 TE Rotterdam (NL) ANDGROWTH FACTOR REVIEWS, OXFORD, GB, vol. 17, no. 3, June 2006 (2006-06), pages 157-171, (74) Representative: Hatzmann, Martin et al XP005482280 ISSN: 1359-6101 Vereenigde • IKENOUE T ET AL: "Inhibitory effects of activin- Johan de Wittlaan 7 A on osteoblast differentiation during cultures of 2517 JR Den Haag (NL) fetal ratcalvarial cells." JOURNAL OF CELLULAR BIOCHEMISTRY 1 NOV 1999, vol. 75, no. 2, 1 (56) References cited: November 1999 (1999-11-01), pages 206-214, WO-A-2006/119406 XP002440166 ISSN: 0730-2312 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 097 515 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 097 515 B1 • HASHIMOTO M ET AL: "Functional regulation of • SAKAI R ET AL: "Activin increases bone mass osteoblastic cells by the interaction of activin-A and mechanical strength of lumbar vertebrae in with follistatin." THE JOURNAL OF BIOLOGICAL aged ovariectomized rats" BONE, PERGAMON CHEMISTRY 5 MAR 1992, vol. 267, no. 7, 5 March PRESS., OXFORD, GB, vol. 27, no. 1, July 2000 1992 (1992-03-05), pages 4999-5004, (2000-07), pages 91-96, XP002294252 ISSN: XP002440167 ISSN: 0021-9258 8756-3282 • HIROTANI H ET AL: "Activin A increases the bone • GADDY-KURTEN D ET AL: "Inhibin suppresses mass of grafted bone in C3H/HeJ mice." and activin stimulates osteoblastogenesis and CALCIFIED TISSUE INTERNATIONAL APR 2002, osteoclastogenesis in murine bone marrow vol. 70, no. 4, April 2002 (2002-04), pages 330-338, cultures.", ENDOCRINOLOGY JAN 2002 LNKD- XP002440168 ISSN: 0171-967X PUBMED:11751595, vol. 143, no. 1, January 2002 (2002-01), pages 74-83, ISSN: 0013-7227 2 EP 2 097 515 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to biologically active compounds for use in methods of treatment and to medi- caments for use in such treatment methods. BACKGROUND TO THE INVENTION 10 [0002] Osteoporosis is a disease in which the density and quality of bone are reduced, leading to weakness of the skeleton and increased risk of fracture, particularly of the spine, wrist, hip, pelvis and upper arm. Osteoporosis and associated fractures are an important cause of mortality and morbidity. Bone quality is a crucial feature in osteoporosis, and osteoblasts play a pivotal role as the bone forming cell and the director of bone resorption by osteoclasts. Osteoblasts have a meschenchymal origin and the differentiation of mesenchymal stem cells to an osteoblastic lineage is regulated 15 by many endocrine, paracrine and autocrine factors. During bone formation osteoblasts produce an organic extracellular matrix (ECM) or osteoid (the immature matrix before mineralizing), which is composed primarily of type I collagen and non-collagenous proteins. This ECM then mineralizes, by the deposition thereon of calcium phosphates, to form bone spicules. Initiation of bone mineralization, or ossification, requires the precipitation and attachment of calcium phosphate crystals, in particular hydroxyapatite (Ca10(PO4)6(OH)2), to the ECM. 20 [0003] This process of mineralization is not unique for bone cells. It also occurs in hypertrophic chondrocytes as part of endochondral bone formation during growth. Furthermore, in pathological conditions of vascular calcification, miner- alization of vascular smooth muscle cell (VSMC) ECM is believed to be involved in vascular calcification as well as in calcification of articular cartilage which occurs with ageing, degenerative joint diseases (e.g. osteoarthritis), and various metabolic and genetic disorders. Thus, ECM mineralization is a physiological process in bone and a pathological one 25 in soft tissues. [0004] Bone mineralization and in particular its regulation is a complicated process controlled by many factors including serum calcium and phosphate concentrations, hormones, enzymes, and the structure of the ECM. The macromolecular organization of type I collagen is a factor facilitating bone mineralization. Initially, calcium phosphate is deposited in the holes of the collagen fibrils and later fills in the pores and the rest of the space within the collagen fibrils. 30 [0005] Vascular calcification, and particular arterial calcification, has long been considered a passive process involving the necrotic core of the plaque serving as a nucleating centre for calcium phosphate mineral deposition. Recent scientific insights have challenged this hypothesis in that genetic aberrations of a variety of extracellular matrix (ECM) molecules, including matrix Gla protein and osteoprotegerin, result in spontaneous arterial calcification, indicating that like bone mineralization, arterial calcification is a delicately regulated process. 35 [0006] It is evident that the possibility of controlling the ECM mineralization process is desired, both in the direction of promoting Mineralization as in the case of osteoporosis and fracture healing, and in the case of reducing or preventing mineralization as in the case of vascular calcification, in particular atherosclerotic calcification, and calcification of car- tilage. [0007] It is an aim of the present invention to provide methods for selecting candidate therapeutic agents for controlling 40 mineralization of an extracellular matrix in a tissue of a subject, Preferably in a mammal, most preferably a human. It is another aim of the present invention to provide methods for controlling ECM mineralization in soft tissue of a mammal, preferably a human, particularly in relation to pathological calcification of cartilage and blood vessels, such as mineral- ization of VSMC produced ECM and atherosclerosis. It is still another aim of the invention to provide methods of control by providing possibilities to stimulate mineralization on the one hand, and by providing possibilities to reduce or prevent 45 mineralization on the other. It is a further aim to provide pharmaceutical compositions and medicaments for use in such methods. SUMMARY OF THE INVENTION 50 [0008] Herein described is a method for selecting a candidate therapeutic agent for controlling mineralization of an extracellular matrix in a tissue of a subject, said method comprising the steps of: a) exposing a cell from said tissue that produces an extracellular matrix to a test compound under conditions that support extracellular matrix formation and matrix maturation; 55 b) determining the expression in said cell of at least one gene in response to said exposure, wherein said gene is selected from group A consisting of genes that encode for thrombospondin 1; collagen type V alpha 1; collagen type XVI alpha 1; collagen type VIII alpha 2; collagen triple helix repeat containing 1; hyaluronan and proteoglycan link protein 1; chondroitin sulfate proteoglycan 2 (versican); latent transforming growth factor beta binding protein 3 EP 2 097 515 B1 2; biglycan; matrix metallopeptidase 2; periostin, osteoblast specific factor; fibulin 5; SPOCK1, Sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican); and ADAM metallopeptidase with thrombospondin type 1 motif; and/or 5 - group B consisting of genes
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