title: Mesenchymal stem cell-dependent formation of heterotopic tendon-bone insertions (osteotendinous junctions).
abstract: Ligament-to-bone and tendon-to-bone interfaces (entheses, osteotendinous junctions [OTJs]) serve to dissipate stress between soft tissue and bone. Surgical reconstruction of these interfaces is an issue of considerable importance as they are prone to injury and the integration of bone and tendon/ligament is in general not satisfactory. We report here the stem cell-dependent spontaneous formation of fibrocartilaginous and fibrous entheses in heterotopic locations of the mouse if progenitors possess a tenogenic and osteo-/chondrogenic capacity. This study followed the hypothesis that enhanced Bone Morphogenetic Protein (BMP)-signaling in adult mesenchymal stem cells that are induced for tendon formation may overcome the tendon-inherent interference with bone formation and may thus allow the stem cell-dependent formation of tendon-bone interfaces. The tenogenic and osteo-/chondrogenic competence was mediated by the adeno- and/or lentiviral expression of the biologically active Smad8 signaling mediator (Smad8ca) and of Bone Morphogenetic Protein 2 (BMP2). Modified mesenchymal progenitors were implanted in subcutaneous or intramuscular sites of the mouse. The stem cell-dependent enthesis formation was characterized histologically by immunohistological approaches and by in situ hybridization. Transplantation of modified murine stem cells resulted in the formation of tendinous and osseous structures exhibiting fibrocartilage-type OTJs, while, in contrast, the viral modification of primary human bone marrow-derived mesenchymal stromal/stem cells showed evidence of fibrous tendon-bone interface formation. Moreover, it could be demonstrated that Smad8ca expression alone was sufficient for the formation of tendon/ligament-like structures. These findings may contribute to the establishment of stem cell-dependent regenerative therapies involving tendon/ligaments and to the improvement of the insertion of tendon grafts at bony attachment sites, eventually.
authors.affiliation: Inflammation and Regeneration, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Shahab-Osterloh
authors.forename: Frank
authors.initials: F
authors.lastname: Witte
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Winkel
authors.forename: Sandra
authors.initials: S
authors.lastname: Laggies
authors.forename: Berit
authors.initials: B
authors.lastname: Neumann
authors.forename: Virginia
authors.initials: V
authors.lastname: Seiffart
authors.forename: Werner
authors.initials: W
authors.lastname: Lindenmaier
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Jochen
authors.initials: J
authors.lastname: Ringe
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.forename: Fritz
authors.initials: F
authors.lastname: Thorey
authors.forename: Elmar
authors.initials: E
authors.lastname: Willbold
authors.forename: Pierre
authors.initials: P
authors.lastname: Corbeau
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D053687:Adult Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002478:Cells, Cultured; D020219:Chondrogenesis; D005260:Female; D051445:Fibrocartilage / Q000254:growth & development* / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009999:Ossification, Heterotopic; D010012:Osteogenesis; D051381:Rats; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism; D013710:Tendons / Q000254:growth & development* / Q000378:metabolism; D013997:Time Factors; D023822:Tissue Engineering; D014161:Transduction, Genetic; D016042:Transplantation, Heterotopic
chemical_list: D055396:Bone Morphogenetic Protein 2; D051904:Smad8 Protein; C109462:Smad9 protein, rat