Zusammenfassung
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 ...
Zusammenfassung
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-2a 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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