204
A. Vortkamp
11.5.4 Noggin Misexpression
To further explore the interaction of IhhlPTHrP signaling with that of
BMPs we have started to use Noggin misexpression as a tool to block
BMP signaling during chondrocyte differentiation. We found that BMP
signaling seems to act at least at three different points during cartilage
differentiation. Firstly, blocking of BMP signaling before limb outgrowth can completely block the formation of the cartilage elements,
indicating the importance of BMP signals for inducing endochondral
ossification (Capdevila and Johnson 1998; McMahon et al. 1998; Merino et al. 1998; Pathi et al. 1999).
Secondly, misexpression of Noggin after the onset oflimb outgrowth
results in extremely shortened cartilage elements. The infection protocol
chosen was such that a considerable expression of Noggin should be
restricted to time points after the condensations have been formed. It has
been hypothesized that BMPs might be involved in mediating the effect
of Ihh signaling in blocking chondrocyte differentiation (Pathi et al.
1999; Zou et al. 1997). If this is true, blocking BMP signaling should
result in advanced hypertrophic differentiation. Instead we found that
the block of BMP signaling at these stages seems to inhibit both chondrocyte proliferation and differentiation. This result can, however, be a
consequence of the third effect we observed after Noggin misexpression: Noggin strongly upregulates BMP4 expression in the perichondrium of the infected skeletal elements especially in the joint region.
Therefore, BMP signaling seems to be regulated by a strong autoregulatory component where blocking of BMP signaling upregulates at least
one BMP gene. This negative feedback loop could also antagonize the
effect of Noggin misexpression on chondrocyte differentiation.
11.6 Conclusions
Endochondral ossification is a complex multistep process which is
regulated by different control systems. Ihh and PTHrP are two signaling
molecules that act together in a negative feedback loop to regulate the
pace of chondrocyte differentiation, one of the critical steps of endochondral ossification. Although both secreted factors were identified as
regulators of the embryonic process of bone development, both continue
A. Vortkamp
11.5.4 Noggin Misexpression
To further explore the interaction of IhhlPTHrP signaling with that of
BMPs we have started to use Noggin misexpression as a tool to block
BMP signaling during chondrocyte differentiation. We found that BMP
signaling seems to act at least at three different points during cartilage
differentiation. Firstly, blocking of BMP signaling before limb outgrowth can completely block the formation of the cartilage elements,
indicating the importance of BMP signals for inducing endochondral
ossification (Capdevila and Johnson 1998; McMahon et al. 1998; Merino et al. 1998; Pathi et al. 1999).
Secondly, misexpression of Noggin after the onset oflimb outgrowth
results in extremely shortened cartilage elements. The infection protocol
chosen was such that a considerable expression of Noggin should be
restricted to time points after the condensations have been formed. It has
been hypothesized that BMPs might be involved in mediating the effect
of Ihh signaling in blocking chondrocyte differentiation (Pathi et al.
1999; Zou et al. 1997). If this is true, blocking BMP signaling should
result in advanced hypertrophic differentiation. Instead we found that
the block of BMP signaling at these stages seems to inhibit both chondrocyte proliferation and differentiation. This result can, however, be a
consequence of the third effect we observed after Noggin misexpression: Noggin strongly upregulates BMP4 expression in the perichondrium of the infected skeletal elements especially in the joint region.
Therefore, BMP signaling seems to be regulated by a strong autoregulatory component where blocking of BMP signaling upregulates at least
one BMP gene. This negative feedback loop could also antagonize the
effect of Noggin misexpression on chondrocyte differentiation.
11.6 Conclusions
Endochondral ossification is a complex multistep process which is
regulated by different control systems. Ihh and PTHrP are two signaling
molecules that act together in a negative feedback loop to regulate the
pace of chondrocyte differentiation, one of the critical steps of endochondral ossification. Although both secreted factors were identified as
regulators of the embryonic process of bone development, both continue