TRANSGLUTAMINASE PROMOTES CPPD DISEASE IN AGING JOINTS

Summary

Principal 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

  1. ncbi The serine protease inhibitor trappin-2 is present in cartilage and synovial fluid in osteoarthritis
    Kanyakorn Jaovisidha
    Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, 53295, USA
    J Rheumatol 33:318-25. 2006
  2. ncbi Calcium crystal deposition and osteoarthritis
    Ann 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
  3. pmc Osteopontin promotes pathologic mineralization in articular cartilage
    Ann 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
  4. ncbi Calcific tendonitis : a model
    Claudia M Gohr
    Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, Wisconsin, USA
    Connect Tissue Res 48:286-91. 2007
  5. pmc Dexamethasone promotes calcium pyrophosphate dihydrate crystal formation by articular chondrocytes
    Mark 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

Scientific Experts

  • Ann K Rosenthal
  • Mark Fahey
  • Claudia M Gohr
  • Kanyakorn Jaovisidha
  • Emily Muth
  • Elizabeth Mitton
  • Koji Yamakawa
  • Bassam T Wakim
  • Ann Etim
  • Ikuko Masuda
  • Nimaradee Boonapatcharoen
  • James Ninomiya

Detail Information

Publications6

  1. ncbi The serine protease inhibitor trappin-2 is present in cartilage and synovial fluid in osteoarthritis
    Kanyakorn Jaovisidha
    Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, 53295, USA
    J Rheumatol 33:318-25. 2006
    ..Yet little is known about matrix-bound serine protease inhibitors or TGase substrates in articular cartilage. Our purpose was to determine if trappin-2 was present in OA cartilage and synovial fluid (SF)...
  2. ncbi Calcium crystal deposition and osteoarthritis
    Ann 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...
  3. pmc Osteopontin promotes pathologic mineralization in articular cartilage
    Ann 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...
  4. ncbi Calcific tendonitis : a model
    Claudia 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...
  5. pmc Dexamethasone promotes calcium pyrophosphate dihydrate crystal formation by articular chondrocytes
    Mark 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...