Study: Regulation of mesenchymal stem cell and chondrocyte differentiation by MIA.
Tscheudschilsuren G, Bosserhoff AK, Schlegel J, Vollmer D, Anton A, Alt V, Schnettler R, Brandt J, Proetzel G.
Source: Scil Proteins GmbH, Heinrich-Damerow-Strasse 1, 06120 Halle/Saale, Germany.
Abstract
Melanoma inhibitory activity (MIA), also referred to as cartilage-derived retinoic acid-sensitive protein (CD-RAP), an 11-kDa secreted protein, is mainly expressed in cartilaginous tissue during embryogenesis and adulthood. Currently, the function of MIA in cartilage tissue is not understood. Here, we describe that MIA acts as a chemotactic factor on the mesenchymal stem cell line C3H10T1/2, stimulating cell migration significantly at concentrations from 0.24 to 240 ng/ml, while inhibiting cell migration at higher doses of 2.4 microg/ml. When analyzing the role of MIA during differentiation processes, we show that MIA by itself is not capable to induce the differentiation of murine or human mesenchymal stem cells. However, MIA influences the action of bone morphogenetic protein (BMP)-2 and transforming growth factor (TGF)-beta 3 during mesenchymal stem cell differentiation, supporting the chondrogenic phenotype while inhibiting osteogenic differentiation. Quantitative RT-PCR analysis revealed the up-regulation of the cartilage markers MIA, collagen type II and aggrecan in human mesenchymal stem cell (HMSC) cultures differentiated in the presence of MIA and TGF-beta 3 or BMP-2 when compared to HMSC cultures differentiated in the presence of TGF-beta 3 or BMP-2 alone. Further, MIA down-regulates gene expression of osteopontin and osteocalcin in BMP-2 treated HMSC cultures inhibiting the osteogenic potential of BMP-2. In the case of human primary chondrocytes MIA stimulates extracellular matrix deposition, increasing the glycosaminoglycan content. Therefore, we postulate that MIA is an important regulator during chondrogenic differentiation and maintenance of cartilage.
Analysis: This paper is most interesting because it shows that there might be certain compounds which have a supporting or even controlling influence on how TGF-Beta and BMPs will affect mesenchymal stem cells.
This compound known as Melanoma Inhibitory Activity (MIA) is very new to me. It is also known as cartilage-derived retinoic acid-sensitive protein (CD-RAP). The fact that is is only expressed during embryogenesis and during adulthood makes me however question whether it is any good at creating cartilage when children are still growing and going through endochondral ossification. Why is this compound not expressed when kids have open growth plates and expressed in adults?
The other thing that I wanted to raise was over the fact that the other name for MIA is retinoic acid sensitive protein. We know that retinoic acid is not good for longitudinal growth. If this compound is sensitive to retinoic acid then maybe it acts like a substrate to the RA to bind to when further cartilage formation is needed to stop ie. full bone maturity.
However the reason why this compound is considered such a breakthrough in the research is that when it is used in combination with TGF-beta or BMP-2, the cartilage tissue cell lineage is differentiated while the bone cell lineage is inhibited.
The MIA, BMP-2, and the TGF-Beta are not enough alone to create the cartilage lineage, although all of them have some type of chondrogenic and osteogenic differentiation potential. With the MIA in as part of a mixture of growth factors, human mesenchymal stem cells seemed to focus only on differentiating in that cartilage lineage. Not only that Collagen Type I markers were found, which is always a good sign.
There was also increased amount of deposition of cartilage extracellular matrix material as well as increased GAG formation.
If I was to create the best chondrogenic growth factor formula, I would definitely be studying much more on this new compound called Melanoma Inhibitory Activity.