Role of the protein SPAG11 in the modulation of experimental arthritis

Abstract

Joint diseases like Osteoarthritis (OA) and Rheumatoid Arthritis (RA) regard to a class of inflammatory diseases highly degenerative, in which the last stage is associated with the irreversible loss of articular cartilage. The Proteinase-Activated Receptor 2 (PAR2) has been hypothesised as a pivotal mediator of joint inflammation, considering that its activation induces joint swelling, leukocyte recruitment, activation of transcription factors like nuclear factor - KB (NFKB) and production of cytokines like IL-1beta and TNF-alpha. This receptor is activated by the proteolysis of its N-terminus by extracellular serine-proteinases like mast cell tryptase. This proteinase, besides its involvement in the process cited above, is also involved in the extracellular matrix turnover, directly via its collagenase activity and indirectly by activating latent metalloproteinases and aggrecanases. On the other hand, it was reported recently that the isoform D of the human SPAG11 gene (sperm associated antigen 11) interacts physically and inhibits competitively the mast cell tryptase. Although SPAG11 isoforms were first cloned from male reproductive tract, preliminary evidences from Dr. Avellar´s group have showed that SPAG11 isoforms are also expressed in hypertrophic condrocytes during the embryonic development of Wistar rat. Interestingly, these are the same cells where PAR2 is highly expressed. Thus, we have hypothesised that products of the SPAG11 gene may be involved in the modulation of extracellular matrix turnover via inhibition of tryptase/PAR2 activity. Therefore, the aim of the present project is to evaluate a putative role of SPAG11 isoforms in the modulation of mouse knee joint synovial inflammation and articular cartilage destruction. (AU)