Interaction of Ihh and BMP/Noggin Signaling during Cartilage Differentiation

Abstract

Bone morphogenetic proteins (BMPs) have been implicated in regulating multiple stages of bone development. Recently it has been shown that constitutive activation of the BMP receptor-IA blocks chondrocyte differentiation in a similar manner as misexpression of Indian hedgehog. In this paper we analyze the role of BMPs as possible mediators of Indian hedgehog signaling and use Noggin misexpression to gain insight into additional roles of BMPs during cartilage differentiation. We show by comparative analysis of BMP and Ihh expression domains that the borders of Indian hedgehog expression in the chondrocytes are reflected in changes of the expression level of several BMP genes in the adjacent perichondrium. We further demonstrate that misexpression of Indian hedgehog appears to directly upregulate BMP2 and BMP4 expression, independent of the differentiation state of the flanking chondrocytes. In contrast, changes in BMP5 and BMP7 expression in the perichondrium correspond to altered differentiation states of the flanking chondrocytes. In addition, Noggin and Chordin, which are both expressed in the developing cartilage elements, also change their expression pattern after Ihh misexpression. Finally, we use retroviral misexpression of Noggin, 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.

Indian hedgehog: Its roles and regulation in endochondral bone development

“…Early studies demonstrated that BMPs when introduced at intramuscular sites in adult mice induce ectopic endochondral bone development [Wozney et al, 1988]. Studies of the roles of this family of proteins in endochondral bone development have been complicated by the large number of BMP proteins that are differentially expressed and regulated in the developing skeleton [ Vortkamp et al, 1996;Pathi et al, 1999]. TGFb and BMPs bind to serine/threonine kinase receptors.…”

“…Within the developing limbs, BMP2, 4, and 7 are expressed in the perichondrium, while BMP6 is found in pre-hypertrophic and hypertrophic chondrocytes [Vortkamp et al, 1996;Pathi et al, 1999]. Zou et al [1997] first reported that overexpressing a constitutively active mutant of BMP type IA receptor induced PTHrP expression in the periarticular perichondrium.…”

“…Based on these data and studies in many different species showing that BMPs are one of the major targets of Hh signaling [Methot and Basler, 1999], it was proposed that BMPs expressed in the perichondrium can act downstream of Ihh. Indeed, ectopic Ihh expression in chicken embryos induced BMPs 2 and 4 in the perichondrium [Pathi et al, 1999], and BMP activation of BMP receptors in the periarticular perichondrium can increase PTHrP expression. However, recent work has refuted the idea that BMP2 or 4 can mediate Ihh regulation of PTHrP.…”

In vivo delivery of fluoresceinated dextrans to the murine growth plate: Imaging of three vascular routes by multiphoton microscopy

“…The Ihh/ PTHrP negative feedback loop acts to put the brakes on at the junction between the end of proliferation and the initiation of hypertrophy, requiring communication between growth plate chondrocytes and the perichondrium (Vortkamp et al, 1996;Long and Linsenmayer, 1998;Pathi et al, 1999;Volk and Leboy, 1999;Pateder et al, 2000;DiNino et al, 2002;Allen et al, 2004). Recent studies provide data that vascular endothelial growth factor (VEGF) alters the permeability characteristics of the vascular endothelium in paracrine regulation of the growth plate involving the perichondrium (Roberts and Palade, 1995;Esser et al, 1998;Zelzer et al, 2002;Ericksson et al, 2003;Aramoto et al, 2004;Cao et al, 2004;Zelzer and Olsen, 2005).…”

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

“…Furthermore, the activity of Notch signaling is mediated by the glycosyltranferase Fringe (Aulehla and Johnson, 1999;Barrantes et al, 1999;Moloney et al, 2000;Zhang and Gridley, 1998), further demonstrating the fine tuning of Notch signaling activity by biochemical mechanisms. Mice with a disruption of the lunatic fringe gene display defects in somite formation as well as in anterior posterior patterning of the somites (Zhang and Gridley, 1998).…”