There are many crucial genes and signaling pathways in the proper development of an organism. Pathologies may arise from a deregulation of these pathways. The Indian Hedgehog-PTH-related
protein (Ihh-
PTHrP) pathway is vital in the proper development of endochondral bones, such as the long bones. The Ihh-
PTHrP pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate. Thus, this pathway allows for the longitudinal growth of bones. However, a disruption in this pathway may lead to
enchondromas and
osteochondromas, which are both childhood cartilaginous
neoplasms. Recently, our lab identified a mutant receptor for
PTHrP in
enchondroma samples. Mice expressing this mutant receptor and mice with increased Ihh activity develop conditions similar to human
enchondromatosis. Linkage analysis shows an association between EXT genes and
osteochondromas in
hereditary multiple exostoses syndrome. Studies in Drosophila and mice suggest EXT gene products play a role in the diffusion of
hedgehog proteins. A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an
osteochondroma. There are agents that inhibit Hedgehog signaling. These agents may be useful in the treatment of
enchondromas and
osteochondromas. This review will discuss the discovery of the Ihh-
PTHrP pathway and its involvement in
neoplasia, and will suggest possible novel therapeutic agents in the treatment of these cartilaginous
neoplasms.