194
A. Vortkamp
showed that Ihh acts in a negative feedback loop preventing not only the
differentiation of hypertrophic chondrocytes but also the differentiation
of the Ihh expressing prehypertrophic chondrocytes themselves (Vortkamp et al. 1996).
11.3.2 Interaction of Ihh and PTHrP
The negative effect of Ihh on chondrocyte differentiation seems to be
mediated by another secreted factor from the perichondrium, Parathyroid Hormone related Protein (PTHrP), (Amizuka et al. 1994; Karaplis
et al. 1994; Lee et al. 1995; Lee et al. 1996; Suva et al. 1987; Weir et al.
1996). PTHrP is most strongly expressed in the joint region of the
developing cartilage elements, whereas its receptor, the PTHIPTHrP
receptor (Juppner et al. 1991; Lanske et al. 1996), is expressed overlapping with and further distal to the domain of Ihh expression. Retroviral
misexpression of Ihh during chick development demonstrated that
PTHrP expression is upregulated by Ihh, indicating that PTHrP acts
downstream of Ihh in regulating chondrocyte differentiation (Vortkamp
et al. 1996). To further investigate the interaction of these signaling
molecules, a mouse limb culture system was used to compare the effect
of hedgehog protein on chondrocyte differentiation in limbs of wildtype mice to that of PTHrP -/- (Vortkamp et al. 1996) or PTH/PTHrP
receptor -/- mice (Lanske et al. 1996). As in the chick, hedgehog protein
blocked chondrocyte differentiation in wild-type mouse limbs, whereas
no block of hypertrophic differentiation could be detected in limbs of
PTHrP -/- or PTHlPTHrP receptor -I-limbs. These experiments strongly
suggest that PTHrP signaling is not only regulated by Ihh but is also
necessary to mediate the effect of Ihh on chondrocyte differentiation
(Lanske et al. 1996; Vortkamp et al. 1996).
11.3.3 Ihh and PTHrP
Regulate the Pace of Chondrocyte Differentiation
What is the role of Ihh and PTHrP signaling during chondrocyte differentiation? One way to interpret the results described above is a model in
which Ihh and PTHrP interact in a negative feedback loop regulating the
A. Vortkamp
showed that Ihh acts in a negative feedback loop preventing not only the
differentiation of hypertrophic chondrocytes but also the differentiation
of the Ihh expressing prehypertrophic chondrocytes themselves (Vortkamp et al. 1996).
11.3.2 Interaction of Ihh and PTHrP
The negative effect of Ihh on chondrocyte differentiation seems to be
mediated by another secreted factor from the perichondrium, Parathyroid Hormone related Protein (PTHrP), (Amizuka et al. 1994; Karaplis
et al. 1994; Lee et al. 1995; Lee et al. 1996; Suva et al. 1987; Weir et al.
1996). PTHrP is most strongly expressed in the joint region of the
developing cartilage elements, whereas its receptor, the PTHIPTHrP
receptor (Juppner et al. 1991; Lanske et al. 1996), is expressed overlapping with and further distal to the domain of Ihh expression. Retroviral
misexpression of Ihh during chick development demonstrated that
PTHrP expression is upregulated by Ihh, indicating that PTHrP acts
downstream of Ihh in regulating chondrocyte differentiation (Vortkamp
et al. 1996). To further investigate the interaction of these signaling
molecules, a mouse limb culture system was used to compare the effect
of hedgehog protein on chondrocyte differentiation in limbs of wildtype mice to that of PTHrP -/- (Vortkamp et al. 1996) or PTH/PTHrP
receptor -/- mice (Lanske et al. 1996). As in the chick, hedgehog protein
blocked chondrocyte differentiation in wild-type mouse limbs, whereas
no block of hypertrophic differentiation could be detected in limbs of
PTHrP -/- or PTHlPTHrP receptor -I-limbs. These experiments strongly
suggest that PTHrP signaling is not only regulated by Ihh but is also
necessary to mediate the effect of Ihh on chondrocyte differentiation
(Lanske et al. 1996; Vortkamp et al. 1996).
11.3.3 Ihh and PTHrP
Regulate the Pace of Chondrocyte Differentiation
What is the role of Ihh and PTHrP signaling during chondrocyte differentiation? One way to interpret the results described above is a model in
which Ihh and PTHrP interact in a negative feedback loop regulating the