Interaction of Ihh and BMP/Noggin Signaling during Cartilage Differentiation

AbstractBone morphogenetic proteins (BMPs) have been implicated in regulating multiple stages of bone development. Recently it has been shown that constitutive activation of theBMP receptor-IAblocks chondrocyte differentiation in a similar manner as misexpression ofIndian hedgehog.In this paper we analyze the role of BMPs as possible mediators of Indian hedgehog signaling and useNogginmisexpression to gain insight into additional roles of BMPs during cartilage differentiation. We show by comparative analysis ofBMPandIhhexpression domains that the borders ofIndian hedgehogexpression in the chondrocytes are reflected in changes of the expression level of severalBMPgenes in the adjacent perichondrium. We further demonstrate that misexpression ofIndian hedgehogappears to directly upregulateBMP2andBMP4expression, independent of the differentiation state of the flanking chondrocytes. In contrast, changes inBMP5andBMP7expression in the perichondrium correspond to altered differentiation states of the flanking chondrocytes. In addition,NogginandChordin,which are both expressed in the developing cartilage elements, also change their expression pattern afterIhhmisexpression. Finally, we use retroviral misexpression ofNoggin,a potent antagonist of BMP signaling, to gain insight into additional roles of BMP signaling during cartilage differentiation. We find that BMP signaling is necessary for the growth and differentiation of the cartilage elements. In addition, this analysis revealed that the members of the BMP/Noggin signaling pathway are linked in a complex autoregulatory network