Thermodynamic profiles of the interactions of suramin, chondroitin sulfate, and pentosan polysulfate with the inhibitory domain of TIMP-3.

ABSTRACT

Extracellular levels of soluble TIMP-3 are low, reflecting its binding by extracellular matrix (ECM) components including sulfated glycosaminoglycans (SGAGs) and endocytosis via low density lipoprotein receptor-related protein 1. Since TIMP-3 inhibits ECM degradation, the ability of SGAGs to elevate extracellular TIMP-3 is significant for osteoarthritis treatment. Previous studies of such interactions have utilized immobilized TIMP-3 or ligands. Here, we report the thermodynamics of the interactions of the sGAG-binding N-domain of TIMP-3 with chondroitin sulfate, pentosan polysulfate, and suramin in solution using isothermal titration calorimetry. All three interactions are driven by a favorable negative enthalpy change combined with an unfavorable decrease in entropy. The heat capacity changes (ΔCp ) for all of the interactions are zero, indicating an insignificant contribution from hydrophobic interactions.