Indian hedgehog (Ihh) and Parathyroid Hormone-related Protein (PTHrP) play a 
critical role in the morphogenesis of the vertebrate skeleton. Targeted deletion 
of Ihh results in short-limbed dwarfism, with decreased chondrocyte 
proliferation and extensive hypertrophy, features shared by mutants in PTHrP and 
its receptor. Activation of Ihh signaling upregulates PTHrP at the articular 
surface and prevents chondrocyte hypertrophy in wild-type but not PTHrP null 
explants, suggesting that Ihh acts through PTHrP. To investigate the 
relationship between these factors during development of the appendicular 
skeleton, mice were produced with various combinations of an Ihh null mutation 
(Ihh(-/-)), a PTHrP null mutation (PTHrP(-/-)), and a constitutively active 
PTHrP/Parathyroid hormone Receptor expressed under the control of the Collagen 
II promoter (PTHrPR*). PTHrPR* rescues PTHrP(-/-) embryos, demonstrating this 
construct can completely compensate for PTHrP signalling. At 18.5 dpc, limb 
skeletons of Ihh, PTHrP compound mutants were identical to Ihh single mutants 
suggesting Ihh is necessary for PTHrP function. Expression of PTHrPR* in 
chondrocytes of Ihh(-/-) mice prevented premature chondrocyte hypertrophy but 
did not rescue either the short-limbed dwarfism or decreased chondrocyte 
proliferation. These experiments demonstrate that the molecular mechanism that 
prevents chondrocyte hypertrophy is distinct from that which drives 
proliferation. Ihh positively regulates PTHrP, which is sufficient to prevent 
chondrocyte hypertrophy and maintain a normal domain of cells competent to 
undergo proliferation. In contrast, Ihh is necessary for normal chondrocyte 
proliferation in a pathway that can not be rescued by PTHrP signaling. This 
identifies Ihh as a coordinator of skeletal growth and morphogenesis, and 
refines the role of PTHrP in mediating a subset of Ihh's actions.