Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

Primary cilia can act as either a negative or positive regulator of the hedgehog (Hh) signaling pathway. Many cartilage tumors are characterized by abnormal activation of the Hh pathway. Here, we report that the presence of primary cilia occurs at a low frequency (12.4%) in neoplastic chondrocytes from malignant human chondrosarcomas, compared with chondrocytes from normal articular cartilage (67.7%). To determine the function of primary cilia in cartilaginous neoplasia, we studied benign cartilage tumors that are formed in mice by chondrocyte-specific overexpression of Gli2, a downstream transcriptional activator of the Hh pathway. Col2A1-Gli2 mice were crossed with Ift88+/− mice, which display a partial loss of ciliogenesis. Surprisingly, cartilage tumors developed in Ift88+/− mice that were phenotypically similar to those that arise in Col2A1-Gli2 mice. Further activation of the Hh pathway was observed in Col2A1-Gli2; Ift88+/− mice compared with either Col2A1-Gli2 or Ift88+/− mice, which was associated with an increased incidence of cartilage tumors. Chondrosarcomas were established in explant cultures, and treated with choral hydrate, which disrupts the functional primary cilia. Thus, treatment resulted in hyperactivity of the Hh signaling pathway, as well as cellular changes that could promote tumor growth. Primary cilia functions to inhibit Hh signaling in neoplastic chondrocytes. The activation of Hh signaling is sufficient to induce benign cartilage tumors without another oncogenic initiating event. Moreover, as primary cilia suppress Hh pathway activation in chondrosarcoma, cellular mechanisms inhibiting proper cilia function may be important in maintaining the neoplastic phenotype.