Abstract
Melanoma inhibitory activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from chondrocytes. It was identified as the prototype of a family of extracellular proteins adopting an SH3 domain-like fold. In order to study the consequences of MIA/CD-RAP deficiency in detail we used mice with a targeted gene disruption of MIA/CD-RAP (MIA−/−) and analyzed cartilage organisation and differentiation in in vivo and in vitro models. Cartilage formation and regeneration was determined in models for osteoarthritis and fracture healing in vivo, in addition to in vitro studies using mesenchymal stem cells of MIA−/− mice. Interestingly, our data suggest enhanced chondrocytic regeneration in the MIA−/− mice, modulated by enhanced proliferation and delayed differentiation. Expression analysis of cartilage tissue derived from MIA−/− mice revealed strong downregulation of nuclear RNA-binding protein 54-kDa (p54nrb), a recently described modulator of Sox9 activity. In this study, we present p54nrb as a mediator of MIA/CD-RAP to promote chondrogenesis. Taken together, our data indicate that MIA/CD-RAP is required for differentiation in cartilage potentially by regulating signaling processes during differentiation.
Highlights
RAP expression starting from the beginning of chondrogenesis and abundant throughout cartilage development.[3,5] melanoma inhibitory activity (MIA)/CD-RAP was revealed to be a specific marker for chondrocytic differentiation.[6]
MIAÀ/À mice developed OA at all, which rose at day 21, but was remarkably reduced till day 42 pointing towards cartilage regeneration
Accelerated proliferation and delayed differentiation in MIAÀ/À murine mesenchymal stem cells. As these models suggest accelerated proliferation of early chondrocytes before differentiation, we examined the effect of loss of MIA/CD-RAP on proliferation of primary mMSC derived from WT and MIAÀ/À littermates
Summary
RAP expression starting from the beginning of chondrogenesis and abundant throughout cartilage development.[3,5] MIA/CD-RAP was revealed to be a specific marker for chondrocytic differentiation.[6]. CD-RAP from the chondroid matrix and can be monitored clinically by enhanced MIA/CD-RAP serum levels.[7,8] Based on its highly restricted activity, the MIA/CD-RAP promoter was used to study transcriptional mechanisms mediating chondrocyte differentiation. We could show that MIA/CD-RAP can influence cartilage differentiation.[11] MIA/CD-RAP was not able to induce chondrocytic differentiation of human mesenchymal stem cells on its own but induced differentiation mediated by transforming growth factor (TGF)-b3 and reverted osteogenic differentiation by BMP2 into more chondrogenic differentiation. We aimed to analyse the molecular function of MIA/CD-RAP in cartilage differentiation using in vivo models for cartilage destruction and regeneration and in vitro models using mesenchymal stem cells of MIAÀ/À mice
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