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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015337-02
Application #
2909687
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1998-05-15
Project End
2003-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Rosenthal, Ann K; Gohr, Claudia M; Uzuki, Miwa et al. (2007) Osteopontin promotes pathologic mineralization in articular cartilage. Matrix Biol 26:96-105
Gohr, Claudia M; Fahey, Mark; Rosenthal, Ann K (2007) Calcific tendonitis : a model. Connect Tissue Res 48:286-91
Jaovisidha, Kanyakorn; Etim, Ann; Yamakawa, Koji et al. (2006) The serine protease inhibitor trappin-2 is present in cartilage and synovial fluid in osteoarthritis. J Rheumatol 33:318-25
Rosenthal, Ann K (2006) Calcium crystal deposition and osteoarthritis. Rheum Dis Clin North Am 32:401-12, vii
Rosenthal, Ann K; Mosesson, Michael W; Gohr, Claudia M et al. (2004) Regulation of transglutaminase activity in articular chondrocytes through thrombin receptor-mediated factor XIII synthesis. Thromb Haemost 91:558-68
Rosenthal, A K; Heinkel, D; Gohr, C M (2003) Thyroxine stimulates transglutaminase activity in articular chondrocytes. Osteoarthritis Cartilage 11:463-70
Jaovisidha, Kanyakorn; Rosenthal, Ann K (2002) Calcium crystals in osteoarthritis. Curr Opin Rheumatol 14:298-302
Derfus, Beth A; Kurian, Jason B; Butler, Jeffrey J et al. (2002) The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol 29:570-4

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