title: Redundancy in regulation of chondrogenesis in MIA/CD-RAP-deficient mice.
abstract: Recent in vitro analysis of MIA/CD-RAP-deficient (MIA(-/-)) mesenchymal stem cells revealed altered chondrogenic differentiation, characterised by enhanced proliferation and delayed differentiation. However, adult MIA(-/-) mice develop normally and show only ultrastructural defects of the cartilage but no major abnormalities. We therefore focused, in this study, on chondrogenesis in vivo in MIA(-/-) mouse embryos to reveal potential molecular changes during embryogenesis and possible redundant mechanisms, which explain the almost normal phenotype despite MIA/CD-RAP loss. In situ hybridisation analysis revealed larger expression areas of Col2a1 and Sox9 positive, proliferating chondrocytes at day 15.5 and 16.5 of embryogenesis in MIA(-/-) mice. The initially diminished zone of Col10a1-expressing hypertrophic chondrocytes at day 15.5 was compensated at day 16.5 in MIA(-/-) embryos. Supported by in vitro studies using mesenchymal stem cells, we discovered that chondrogenesis in MIA(-/-) mice is modified by enhanced Sox9, Sox6 and AP-2α expression. Finally, we identified reduced AP1 and CRE activity, analysed by reporter gene- and electrophoretic mobility shift assays, important for redundancy mechanism which rescued delayed hypertrophic differentiation and allows normal development of MIA(-/-) mice. In summary, as observed in other knockout models of molecules important for cartilage development and differentiation, viability and functional integrity is reached by remarkable molecular redundancy in MIA/CD-RAP knockout mice.
authors.affiliation: University of Regensburg Medical School, Institute of Pathology, D-93053 Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schmid
authors.affiliation: University of Regensburg Medical School, Institute of Pathology, D-93053 Regensburg, Germany. Electronic address: anja.bosserhoff@klinik.uni-regensburg.de.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D020219:Chondrogenesis / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic
chemical_list: D016326:Extracellular Matrix Proteins; C513263:Mia protein, mouse
keywords: Cell signalling; Chondrogenesis; Differentiation; MIA-knockout mouse; MIA/CD-RAP; Sox9