Detection of c-fos expression in benign and malignant musculoskeletal lesions. The proto-oncogene c-fos has been implicated in the development of both benign and malignant lesions of bone. Although c-fos expression in such lesions has been well studied in transgenic mouse models, less is known about its role in human musculoskeletal pathology. To clarify this relationship, we used in situ hybridization to localize c-fos m-RNA transcripts in 26 fibrous lesions (eight cases of extra-abdominal fibromatosis and six cases each of fibrous dysplasia, fibrosarcoma, and malignant fibrous histiocytoma of bone) as well as six chondrosarcomas and eight conventional high grade osteosarcomas. We found detectable levels of c-fos expression in tissues from each type of lesion tested. Moreover, all fibrous lesions consistently demonstrated high levels of expression in a majority of cells in each lesion. Chondrosarcomas and osteosarcomas exhibited more heterogeneity in c-fos expression than fibrous tissues. Three of six chondrosarcomas showed moderate expression of c-fos while only one of six was considered high. Similarly, only three of eight osteosarcomas had high expression of c-fos. These findings indicate that the expression of c-fos may be important in the development of a broad range of fibrous lesions as well as in bone and cartilaginous tumors. Additionally, this is the first report, to our knowledge, of detectable c-fos m-RNA in human chondrosarcoma.