The main objective of this study was to characterize the cellular phenotypes in the repair tissue of full-thickness defects of articular cartilage by histologic and molecular biologic techniques. Healing of the defects in the articular cartilage of the knee joints of 12 rabbits was analyzed at days 3, 7, 14, 28 and 50 using histology and Northern analysis of mRNA levels for type I, II and III collagens and osteonectin. The cellular source of each mRNA was determined by in situ hybridization. Two novel cDNA clones for rabbit type II and III collagen mRNAs were constructed to obtain species-specific hybridization probes. The repair tissue of full-thickness defects consisted of two types of tissue. At the bottom of the defect, bone-derived cells with high levels of type I collagen and osteonectin mRNA were actively producing new osteoid, while superficially a slow transition from a fibrin clot into undifferentiated mesenchyme with cells containing type III collagen mRNA was observed. This tissue subsequently became fibrocartilaginous, with small groups of cells turning on the transcription of the type II collagen gene and acquiring a phenotype typical for hyaline cartilage. The data suggest that small clusters of cells in the repair tissue of full-thickness articular cartilage defects are capable of turning on an apparently correct chondrocytic phenotype. The low transcription level of the type II collagen gene suggests, however, that insufficient amounts of fundamentally important regulatory factors or progenitor cells are present in the repair tissue. In the future, such factors should be administrable into the joint by novel therapeutic means.