title: Matrilin-3 switches from anti- to pro-anabolic upon integration to the extracellular matrix.
abstract: The extracellular matrix (ECM) has long been viewed primarily as an organized network of solid-phase ligands for integrin receptors. During degenerative processes, such as osteoarthritis, the ECM undergoes deterioration, resulting in its remodeling and in the release of some of its components. Matrilin-3 (MATN3) is an almost cartilage specific, pericellular protein acting in the assembly of the ECM of chondrocytes. In the past, MATN3 was found required for cartilage homeostasis, but also involved in osteoarthritis-related pro-catabolic functions. Here, to better understand the pathological and physiological functions of MATN3, its concentration as a circulating protein in articular fluids of human osteoarthritic patients was determined and its functions as a recombinant protein produced in human cells were investigated with particular emphasis on the physical state under which it is presented to chondrocytes. MATN3 down-regulated cartilage extracellular matrix (ECM) synthesis and up-regulated catabolism when administered as a soluble protein. When artificially immobilized, however, MATN3 induced chondrocyte adhesion via a α5β1 integrin-dependent mechanism, AKT activation and favored survival and ECM synthesis. Furthermore, MATN3 bound directly to isolated α5β1 integrin in vitro. TGFβ1 stimulation of chondrocytes allowed integration of exogenous MATN3 into their ECM and ECM-integrated MATN3 induced AKT phosphorylation and improved ECM synthesis and accumulation. In conclusion, the integration of MATN3 to the pericellular matrix of chondrocytes critically determines the direction toward which MATN3 regulates cartilage metabolism. These data explain how MATN3 plays either beneficial or detrimental functions in cartilage and highlight the important role played by the physical state of ECM molecules.
authors.affiliation: UMR 7561 CNRS-Université de Lorraine, Faculté de Médecine, 9, Avenue de la Forêt de Haye, BP 184, 54505 Vandoeuvre-lès-Nancy, France. Jean-Baptiste.Vincourt@medecine.uhp-nancy.fr
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vincourt
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Etienne
authors.forename: Laurent
authors.initials: L
authors.lastname: Grossin
authors.forename: Justine
authors.initials: J
authors.lastname: Cottet
authors.forename: Claudie
authors.initials: C
authors.lastname: Bantsimba-Malanda
authors.forename: Patrick
authors.initials: P
authors.lastname: Netter
authors.forename: Didier
authors.initials: D
authors.lastname: Mainard
authors.forename: Virginie
authors.initials: V
authors.lastname: Libante
authors.forename: Pierre
authors.initials: P
authors.lastname: Gillet
authors.forename: Jacques
authors.initials: J
authors.lastname: Magdalou
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008297:Male; D064235:Matrilin Proteins; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D012995:Solubility; D013582:Synovial Fluid / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D039081:Integrin alpha5beta1; D064235:Matrilin Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1