Role of deleted in colon carcinoma in osteoarthritis and in chondrocyte migration

Abstract

The concept of the chondrocyte as a stationary cell surrounded by an apparently impenetrable matrix has been challenged by in vitro observations in recent years. Chondrocyte migration may have a role in remodelling of the cartilage and pathological conditions. Candidate molecules are repellent factors for the regulation of chondrocyte migration, which are expressed in fetal and adult cartilage. We analysed the potential role of the receptor deleted in colon carcinoma (DCC) in chondrocytes, as this may exert attractive activities. Gene expression was determined by quantitative RT-PCR and immunohistochemistry, and gene regulation by electro mobility shift assay and chromatin immunoprecipitation. Functional assays on migration and differentiation were done after cell treatment and transfection. DCC was shown to be specifically up-regulated in OA compared with normal chondrocytes in vitro and in vivo. Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. Netrin-1, the ligand of DCC, was revealed to induce the migration of OA chondrocytes specifically. Expression of DCC in healthy chondrocytes by transient transfection significantly induced cell migration and chemotaxis to Netrin-1. DCC expression had no influence on cell differentiation; however, induction of MMP1 and -3 expression was observed. Strong differential expression of DCC in OA compared with normal chondrocytes hints of a possible role of DCC in the pathophysiology of OA. The strong impact of the DCC receptor on cellular mobility of chondrocytes in vitro suggests a major relevance of migratory activities in physiological and pathological conditions of cartilage. However, definite proof of chondrocyte movements in vivo still has to be established.