Article Text

Advanced Glycation End Products Increase Transglutaminase Activity in Primary Porcine Tenocytes
  1. Ann K. Rosenthal, MD*,
  2. Claudia M. Gohr, BS*,
  3. Elizabeth Mitton, MS*,
  4. Vincent Monnier, MD,
  5. Todd Burner, MD*
  1. From the *Department of Medicine, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, WI; and †Department of Pathology, Case Western Reserve University, Cleveland, OH.
  1. Received September 18, 2008, and in revised form October 30, 2008.
  2. Accepted for publication November 10, 2008.
  3. Reprints: Ann K. Rosenthal, MD, Rheumatology Section/cc-111W, Zablocki VA Medical Center, 5000 W. National Ave, Milwaukee, WI 53295-1000 (e-mail: akrose{at}


Objectives Tendon abnormalities, such as increased stiffness, thickness, and excess calcification, occur commonly in patients with diabetes mellitus and cause considerable disability. These changes are frequently attributed to increased cross-linking of extracellular matrix components by advanced glycation end-products (AGEs). However, cellular effects of AGEs, such as increased activity of the cross-linking transglutaminase (Tgase) enzymes, could also contribute to altered tissue biomechanics and calcification in diabetic tendons. We determined the effect of AGE-modified protein on tenocyte Tgase activity.

Research Design and Methods Primary porcine tenocytes were exposed to Nε- carboxymethyl-lysine (CML)-modified type I collagen in high or normal glucose media. Protein and mRNA levels of the Tgase enzymes and Tgase activity levels were measured, as were markers of apoptosis. We also determined the effect of antioxidants on CML-collagen mediated Tgase activity.

Results Carboxymethyl-lysine-collagen increased Tgase activity in tenocytes 2.3- to 5.6-fold over unmodified collagen controls in both normal and high glucose media, without altering enzyme protein levels. Anti-oxidant treatment reduced the effect of CML-collagen on Tgase activity. Deoxyribonucleic acid laddering and annexin V protein levels were not altered by CML-collagen exposure.

Conclusions Carboxymethyl-lysine-collagen increased Tgase activity in tenocytes, likely posttranslationally. Increased levels of Tgase-mediated cross-links may contribute to the excess calcification and biomechanical pathology seen in diabetic tendons.

Key Words
  • tendinopathy
  • diabetes mellitus
  • advanced glycation end-products
  • transglutaminases
  • factor XIIIA

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