Interaction of Ihh and BMP Noggin signaling during cartilage differentiation

Bone morphogenetic proteins (BMPs) have been implicated in regulating multi ple stages of bone development. Recently it has been shown that constitutiv e activation of the BMP receptor-IA blocks chondrocyte differentiation in a similar manner as misexpression of Indian hedgehog. In this paper we analy ze the role of BMPs as possible mediators of Indian hedgehog signaling and use Noggin misexpression to gain insight into additional roles of BMPs duri ng cartilage differentiation. We show by comparative analysis of BMP and Ih h expression domains that the borders of Indian hedgehog expression in the chondrocytes are reflected in changes of the expression level of several BM P genes in the adjacent perichondrium. We further demonstrate that misexpre ssion of Indian hedgehog appears to directly upregulate BMP2 and BMP4 expre ssion, independent of the differentiation state of the flanking chondrocyte s. In contrast, changes in BMP5 and BMP7 expression in the perichondrium co rrespond to altered differentiation states of the flanking chondrocytes. In addition, Noggin and Chordin, which are both expressed in the developing c artilage elements, also change their expression pattern after Ihh misexpres sion. Finally, we use retroviral misexpression of Noggin, a potent antagoni st 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. (C) 1999 Academic Press.