Chondrocyte hypertrophy is an essential process required for endochondral bone 
formation. Proper regulation of chondrocyte hypertrophy is also required in 
postnatal cartilage homeostasis. Indian hedgehog (Ihh) and PTHrP signaling play 
crucial roles in regulating the onset of chondrocyte hypertrophy by forming a 
negative feedback loop, in which Ihh signaling regulates chondrocyte hypertrophy 
by controlling PTHrP expression. To understand whether there is a 
PTHrP-independent role of Ihh signaling in regulating chondrocyte hypertrophy, 
we have both activated and inactivated Ihh signaling in the absence of PTHrP 
during endochondral skeletal development. We found that upregulating Ihh 
signaling in the developing cartilage by treating PTHrP(-/-) limb explants with 
sonic hedgehog (Shh) protein in vitro, or overexpressing Ihh in the cartilage of 
PTHrP(-/-) embryos or inactivating patched 1 (Ptch1), a negative regulator of 
hedgehog (Hh) signaling, accelerated chondrocyte hypertrophy in the PTHrP(-/-) 
embryos. Conversely, when Hh signaling was blocked by cyclopamine or by removing 
Smoothened (Smo), a positive regulator of Hh signaling, chondrocyte hypertrophy 
was delayed in the PTHrP(-/-) embryo. Furthermore, we show that upregulated Hh 
signaling in the postnatal cartilage led to accelerated chondrocyte hypertrophy 
during secondary ossification, which in turn caused reduction of joint 
cartilage. Our results revealed a novel role of Ihh signaling in promoting 
chondrocyte hypertrophy independently of PTHrP, which is particularly important 
in postnatal cartilage development and homeostasis. In addition, we found that 
bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling in the cartilage 
may both mediate the effect of upregulated Ihh signaling in promoting 
chondrocyte hypertrophy.