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| TRANSGLUTAMINASE PROMOTES CPPD DISEASE IN AGING JOINTSSummaryPrincipal Investigator: Ann Rosenthal Affiliation: Medical College of Wisconsin Country: USA Abstract: DESCRIPTION (Adapted from the Applicant's Abstract): Calcium pyrophosphate dihydrate (CPPD) deposition disease is a common form of degenerative arthritis that preferentially affects the elderly. The causes of CPPD crystal formation in aging articular cartilage are unknown, although many similarities exist between processes of normal cartilage mineralization in growth plate and those of pathologic mineralizing causing CPPD disease. Current evidence suggests that CPPD crystal formation results from excess elaboration of inorganic pyrophosphate (PPi) by chondrocytes, and occurs in or around articular cartilage vesicles (ACVs) and at sites of altered cartilage matrix. The processes known to promote CPPD crystal formation are strongly and uniquely enhanced by transforming growth factor beta (TGF-beta), which is stored in cartilage matrix in a latent biologically inactive form (LTGF-beta). The enzyme transglutaminase (TGase) catalyzes a unique post-translational modification of proteins, resulting in diverse biological effects in various tissues. TGase has recently been identified in mineralizing growth plate chondrocytes. Although TGase participates in processes of cell aging and LTGF-beta activation in other tissues, its role in articular cartilage remains undefined. The applicant's laboratory discovered strikingly high levels of active TGase and type II TGase protein in articular chondrocytes from old pigs compared to chondrocytes from young pigs. Inhibitors of TGase suppress PPi elaboration and reduce levels of activated TGF-beta secreted by old chondrocytes, conditions unfavorable to the formation of CPPD crystals. It is hypothesized that increased TGase activity in aging articular cartilage leads to CPPD crystal formation and the resultant degenerative arthritis. As a consequence, this application proposes to: 1) examine the function of TGase in CPPD deposition by exploring its role in LTGF-beta activation, extracellular matrix modulation, and ACV-induced mineralization in a porcine model; 2) explore the regulation of TGase activity in porcine articular cartilage by factors which modulate CPPD crystal formation; and 3) extend these findings to aging human articular cartilage and cartilage affected by CPPD disease. The goal of these studies is to understand the role and regulation of TGase in aging articular cartilage as it relates to CPPD deposition disease. This multifunctional enzyme represents a novel target for new pharmacologic agents directed against this common degenerative disease affecting our rapidly aging population. Funding Period: 1998-05-15 - 2004-04-30 more information: NIH RePORT Top Publications
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The serine protease inhibitor trappin-2 is present in cartilage and synovial fluid in osteoarthritisKanyakorn Jaovisidha
Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, 53295, USA
J Rheumatol 33:318-25. 2006..CONCLUSION: We confirmed the presence of trappin-2 in OA cartilage and SF. Elevated levels of TGase activity in OA cartilage may increase levels of this serine protease inhibitor in response to injury...- Calcium crystal deposition and osteoarthritisAnn K Rosenthal
Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
Rheum Dis Clin North Am 32:401-12, vii. 2006..Further research in this area will improve understanding of the pathogenesis of these conditions and should lead to the development of effective therapy for all types of degenerative arthritis... 
Osteopontin promotes pathologic mineralization in articular cartilageAnn K Rosenthal
The Division of Rheumatology, Department of Medicine, Medical College of Wisconsin and the Zablocki VA Medical Center, Milwaukee, WI 53295 1000, USA
Matrix Biol 26:96-105. 2007..Thus, osteopontin may play an important role in facilitating CPPD crystal formation in articular cartilage...- Calcific tendonitis : a modelClaudia M Gohr
Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, Wisconsin, USA
Connect Tissue Res 48:286-91. 2007..Matrix vesicles isolated from tendons mineralize in vitro. This model may aid in the study of the pathogenesis of calcific tendonitis as well as serve as a means to identify effective therapies for this common disorder... - Dexamethasone promotes calcium pyrophosphate dihydrate crystal formation by articular chondrocytesMark Fahey
Department of Medicine, Medical College of Wisconsin, Rheumatology Section, cc 111W, Zablocki VA Medical Center, 5000 W National Ave, Milwaukee, WI 53295 1000, USA
J Rheumatol 36:163-9. 2009..Dxm has variable effects in mineralization models. We investigated the effects of Dxm on CPPD crystal formation in a well established tissue culture model...