Aggrecan is one of the most abundant components of the articular cartilage matrix and its degradation by aggrecanases is considered to be a key early event in the development of osteoarthritis. This study investigates whether the extracellular level of ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs-4), one of the most studied aggrecanases, can be regulated by receptor-mediated endocytosis. Exogenously-added ADAMTS-4 disappeared from the medium of HTB94 cells and TCA-soluble degradation products of ADAMTS-4 increased in the medium over time. Fluorescent-labeled ADAMTS-4 could be detected within the cell by confocal microscopy. ADAMTS-4 clearance by HTB94 cells and chondrocytes could be inhibited by more than 70 % by heparin and another sulfated glycan, calcium pentosan polysulfate, suggesting that the cellular uptake of ADAMTS-4 was via a mechanism involving cell surface heparan sulfate proteoglycans (HSPGs). GM6001 also inhibited ADAMTS-4 clearance by 50 %, suggesting that cell surface metalloprotease-mediated degradation played a contributory role. However, ADAMTS-4 clearance was reduced by 50 % in a HSPG-deficient cell line compared to wild-type cells, further supporting a HSPG-dependent mechanism of ADAMTS-4 cellular uptake and preliminary studies using Timp-3-null fibroblasts suggest that ADAMTS-4 may be endocytosed in a complex with TIMP-3. In HTB94 cells and chondrocytes, the appearance of TCA-soluble degradation products was also inhibited by at least 50 % by receptor-associated protein (RAP), an antagonist for members of the low-density lipoprotein receptor (LDL-R) family. However, siRNA knockdown of LDL-receptor-related protein (LRP-1), a member of the LDL-R family, in HTB94 cells and the use of an LRP-1-deficient cell line had no affect on the clearance of ADAMTS-4. These results suggest that another member of the LDL-R family may be involved. Taken together, this research has revealed a novel RAP-sensitive and/or HSPG-sensitive mechanism of ADAMTS-4 regulation which may have a role in the degradation of the cartilage matrix.