Murine Progressive Ankylosis (MPA), is a spontaneous disorder in mice resulting from an autosomal recessive genetic mutation (a n k) on chromosome 15. It begins as a proliferative synovitis which evolves into chondroid metaplasia and enchondral ossification with ankylosis of peripheral joints and axial skeleton. MPA is dramatically similar to ankylosing spondylitis. Extensive studies indicate that the disease is not immunologically mediated. Disease progression and joint ankylosis in MPA is strikingly inhibited by early treatment with phosphocitrate (PC). This inhibition is accompanied by a decrease in synovial proliferation and persists 2-3 weeks after discontinuation of therapy. PC is known to modulate intracellular calcium levels and inhibit calcium accumulation in matrix vesicles in other systems. The mechanism(s) by which PC inhibits MPA disease progression remain to be identified. We have preliminary data which indicates that spinal ligament fibroblasts from MPA mice proliferate in vitro to a greater extent than nonaffected controls when stimulated with TGFbeta. PC inhibits this hyperresponsiveness to TGFbeta at doses of 10-3 M. The overall goal of this project is to define the pathogenic mechanisms responsible for the excessive bone production in MPA. The striking in vivo inhibitory effects of phosphocitrate on MPA disease progression and the altered in vitro proliferative responses of spinal ligament fibroblasts to TGFbeta, an important osteogenic growth factor, are important clues to understanding the cellular processes that produce ankylosis in this model. We plan to define mechanisms responsible for this altered in vitro proliferation in MPA fibroblasts by: 1) characterizing the TGFbeta receptor(s) present on MPA and normal spinal ligament fibroblasts and 2) defining their function and relationship to development in articular tissues.