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

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.

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