Among the many forms of arthritis a substantial portion shows a familial aggregation, with some showing definite mendelian patterns of inheritance. Included are some of the major causes of disability, yet only in the past decade and a half has a start been made in the identification of specific and biochemical abnormalities of metabolism that are responsible and in the delineation of the specific mechanisms that lead to clinical expression of arthritis. The practical value of such an approach is well demonstrated in the case of gouty arthritis. A detailed understanding of the pathogenetic mechanism responsible provided the basis for rational and effective therapeutic intervention; consequently this disease is no longer a significant cause of disability in this country. In ochronotic arthritis, where the primary genetic and enzyme defect producing alcaptonuria has been well defined, the detailed molecular mechanism by which the accumulating homogentisic acid produces the clinical symptoms of ochronotic arthritis in adult life remains obscure. Work on familial chondrocalcinosis, supported by the grant, has shown an increased pyrophosphate content in cells cultured from patients of a large kindred with this disease. Both the genetic and enzyme defect responsible for the increased pyrophosphate concentration and the mechanism of pyrophosphate crystal formation in their cartilage remains to be elucidated. Specific objectives of the proposed research will be to identify additional genetic and biochemical factors underlying the various types of heritable arthritis, to determine the mechanism by which the biochemical lesion leads to the pathological process and to devise more rational forms of thereapeutic intervention by nutritional or pharmacological agents to prevent the pathology. Studies will first be made in vitro at the molecular, biochemical and cellular level using fibroblasts and permanent lymphoblast lines, as well as cultured chondrocytes from affected patients. Promising approaches in vitro will then be extended to clinical studies of patients in vivo through the increased understanding of the fundamental nature of the disorder.