The Hedgehog (Hh) family of proteins consists of Indian hedgehog (Ihh), sonic 
hedgehog (Shh), and desert hedgehog (Dhh). These proteins serve as essential 
regulators in a variety of developmental events. Ihh is mainly produced and 
secreted by prehypertrophic chondrocytes and regulates chondrocyte hypertrophy 
and endochondral bone formation during growth plate development. Tissue-specific 
deletion of the Ihh gene (targeted by Col2a1-Cre) causes early lethality in 
mice. Transgenic mice with induced Ihh expression exhibit increased chondrocyte 
hypertrophy and cartilage damage resembling human osteoarthritis (OA). During OA 
development, chondrocytes recapitulate the differentiation process that happens 
during the fetal status and which does not occur to an appreciable degree in 
adult articular cartilage. Ihh expression is up-regulated in human OA cartilage, 
and this upregulation correlates with OA progression and changes in chondrocyte 
morphology. A genetic study in mice further showed that conditional deletion of 
Ihh in chondrocytes attenuates OA progression, suggesting the possibility that 
blocking Ihh signaling can be used as a therapeutic approach to prevent or delay 
cartilage degeneration. However, Ihh gene deletion is currently not a 
therapeutic option as it is lethal in animals. RNA interference (RNAi) provides 
a means to knockdown Ihh without the severe side effects caused by chemical 
inhibitors. The currently available delivery methods for RNAi are nanoparticles 
and liposomes. Both have problems that need to be addressed. In the future, it 
will be necessary to develop a safe and effective RNAi delivery system to target 
Ihh signaling for preventing and treating OA.