The covalent complex formation of hyaluronan with heavy chains of inter-α-trypsin inhibitor family is important for its functions

In culture, not all, but most cells form a hyaluronan (HA)-rich matrix around themselves. In a typical case, chondrocytes in serum-supplemented culture elaborate the matrix consisting of hyaluronan (HA), hyaluronan-binding chondroitin sulfate proteoglycans such as aggrecan and PG-M/versican, and the Serum-derived Hyaluronan-Associated Proteins, which we previously named SHAP [1]. We found that SHAP exactly corresponds to the heavy chains of the serum inter-alpha-trypsin inhibitor (ITI) family molecules, and is covalently bound to HA. The structure of the SHAP-HA complex and a possible pathway of its formation are shown in Figure 1 [2, 3]. ITI family molecules comprise a common subunit, bikunin and one or two of the three genetically distinct, but related heavy chains which are covalently attached to the chondroitin sulfate chain of bikuninviaan ester bond of the same type as the one found in the SHAP-HA complex [4]. Accumulated evidence by us [1,5,6] and others [7] shows that the SHAP-HA complex is formed by replacing the chondroitin sulfate portion of ITI family molecules by HA with concomitant release of bikunin. The reaction needs at least intact forms of ITI family molecules and HA as substrates and a serum factor(s) as an enzyme. Since ITI family molecules are synthesized in the liver and secreted into the blood at the high concentrations (0.15-0.5 mg/ml in human), the SHAP-HA complex will be formed in any HA-containing tissue whenever it happens to encounter blood.