Rat liver sinusoidal endothelial cells (LECs) express two hyaluronan (HA) receptors, of 175 and 300 kDa, responsible for the endocytic clearance of HA. We have characterized eight monoclonal antibodies (mAbs) raised against the 175-kDa HA receptor partially purified from rat LECs. These mAbs also cross-react with the 300-kDa HA receptor. The 175-kDa HA receptor is a single protein, whereas the 300-kDa species contains three subunits, ␣, ␤, and ␥ at 260, 230, and 97 kDa, respectively (Zhou, B., Oka, J. A., and Weigel, P. H. (1999) J. Biol. Chem. 274, 33831-33834). The 97-kDa subunit was not recognized by any of the mAbs in Western blots. Based on their cross-reactivity with these mAbs, the 175-, 230-, and 260-kDa proteins appear to be related. Two of the mAbs inhibit 125 I-HA binding and endocytosis by LECs at 37°C. All of these results confirm that the mAbs recognize the bone fide LEC HA receptor. Indirect immunofluoresence shows high protein expression in liver sinusoids, the venous sinuses of the red pulp in spleen, and the medullary sinuses of lymph nodes. Because the tissue distribution for this endocytic HA receptor is not unique to liver, we propose the name HARE (HA receptor for endocytosis). HA1 is an important and often abundant extracellular matrix component of all tissues, in particular cartilage, skin, and vitreous humor (1). HA plays a key role in development, morphogenesis, and differentiation, in cell adhesion and proliferation, and in inflammation and wound healing (1-4). In humans the total body turnover of HA is several grams per day (1). Although local turnover of HA occurs in avascular tissues, particularly cartilage (5, 6), two major clearance systems are responsible for HA degradation and removal in the body (4). The first is the lymphatic system, which accounts for ϳ85% of the HA turnover, and the second is in the liver, which accounts for the other ϳ15% of the total body HA turnover. Throughout the body, HA is continuously synthesized and degraded in almost all tissues. At the same time, chondroitin sulfate and other glycosaminoglycans are also released from the cleavage of proteoglycans, especially aggregating proteoglycans associated with HA. Large native HA molecules (ϳ10 7 Da) are partially degraded to large fragments (ϳ10 6 Da) that are released from the matrix and enter the lymphatic system, flowing to lymph nodes.The lymph nodes completely degrade the majority of HA (ϳ85%) by unknown mechanisms. Neither the responsible cell type, the receptor involved, nor the location in lymph nodes at which HA uptake and degradation occurs has been determined. The remaining HA (ϳ15%) that escapes degradation in the lymph nodes ultimately flows into the blood at the thoracic duct. Since HA is an exceptionally viscous polysaccharide in solution, it would be deleterious for the blood concentration of HA, even at relatively low molecular weight, to increase. Clearance of this circulating HA and the other glycosaminoglycan degradation fragments is presumably important for normal health (1, 4). Elevate...