The Indian Hedgehog - PTHrP System in Bone Development
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pression. If Ihh directly regulates the expression of BMP genes, ectopic
Ihh expression should lead to a BMP expression pattern throughout the
perichondrium that reflects the pattern normally flanking the Ihh expression domain in the prehypertrophic chondrocytes. If only dependent on
Ihh, this expression pattern should be independent of the stage of chondrocyte differentiation. Alternatively, the correlation between BMP and
Ihh expression domains could be established by other signals from the
chondrocytes, which regulate Ihh and BMP expression independently.
In that case, ectopic expression of Ihh should lead to a BMP expression
level throughout the perichondrium which reflects the differentiation
state of the adjacent chondrocytes. As Ihh misexpression blocks chondrocyte differentiation before they reach the prehypertrophic state, the
expression of the BMP genes should resemble the expression that is
normally found flanking the proliferating cells.
We found by misexpression of Ihh that BMP5, BMP6, and BMP7 are
not directly regulated by Ihh, but rather their expression seems to be
dependent on the differentiation state of the chondrocytes: BMP6 and
BMP7 expression is downregulated and BMP5 expression is upregulated.
In contrast, the expression of BMP2 and BMP4 is strongly upregulated upon Ihh misexpression independent of the state of chondrocyte
differntiation. These BMP genes are normally most strongly expressed
in the perichondrium flanking the Ihh expressing prehypertrophic and
hypertrophic chondrocytes, and weaker outside this region. Ihh misexpression results in strong induction of BMP2 and BMP4 expression in
the perichondrium flanking proliferating chondrocytes, when these express high levels of Ihh. Therefore, these two BMP genes are good
candidates for being direct targets of Ihh signaling.
Ihh expression has been shown to regulate PTHrP expression in the
periarticular perichondrium (Vortkamp et al. 1996). However, as hedgehog molecules are not thought to travel over long distances, secondary
molecules seem to be required to mediate the Ihh signal from the
prehypertrophic chondrocytes to the periarticular perichondrium. In
combination with the results of Zou et al. (1997), BMP2 and BMP4 but
not BMP5, BMP6, or BMP7 might be good candidates to serve as these
secondary signals. They could then act through BMPR-IA, which is
expressed in the perichondrium of the joint, to induce PTHrP (Fig. 4).
201
pression. If Ihh directly regulates the expression of BMP genes, ectopic
Ihh expression should lead to a BMP expression pattern throughout the
perichondrium that reflects the pattern normally flanking the Ihh expression domain in the prehypertrophic chondrocytes. If only dependent on
Ihh, this expression pattern should be independent of the stage of chondrocyte differentiation. Alternatively, the correlation between BMP and
Ihh expression domains could be established by other signals from the
chondrocytes, which regulate Ihh and BMP expression independently.
In that case, ectopic expression of Ihh should lead to a BMP expression
level throughout the perichondrium which reflects the differentiation
state of the adjacent chondrocytes. As Ihh misexpression blocks chondrocyte differentiation before they reach the prehypertrophic state, the
expression of the BMP genes should resemble the expression that is
normally found flanking the proliferating cells.
We found by misexpression of Ihh that BMP5, BMP6, and BMP7 are
not directly regulated by Ihh, but rather their expression seems to be
dependent on the differentiation state of the chondrocytes: BMP6 and
BMP7 expression is downregulated and BMP5 expression is upregulated.
In contrast, the expression of BMP2 and BMP4 is strongly upregulated upon Ihh misexpression independent of the state of chondrocyte
differntiation. These BMP genes are normally most strongly expressed
in the perichondrium flanking the Ihh expressing prehypertrophic and
hypertrophic chondrocytes, and weaker outside this region. Ihh misexpression results in strong induction of BMP2 and BMP4 expression in
the perichondrium flanking proliferating chondrocytes, when these express high levels of Ihh. Therefore, these two BMP genes are good
candidates for being direct targets of Ihh signaling.
Ihh expression has been shown to regulate PTHrP expression in the
periarticular perichondrium (Vortkamp et al. 1996). However, as hedgehog molecules are not thought to travel over long distances, secondary
molecules seem to be required to mediate the Ihh signal from the
prehypertrophic chondrocytes to the periarticular perichondrium. In
combination with the results of Zou et al. (1997), BMP2 and BMP4 but
not BMP5, BMP6, or BMP7 might be good candidates to serve as these
secondary signals. They could then act through BMPR-IA, which is
expressed in the perichondrium of the joint, to induce PTHrP (Fig. 4).