Abstract
Matrix metalloproteinase 13 (MMP-13) degrades collagenous extracellular matrix and its aberrant activity associates with diseases such as arthritis, cancer, atherosclerosis and fibrosis. The wide range of MMP-13 proteolytic capacity suggests that it is a powerful, potentially destructive proteinase and thus it has been believed that MMP-13 is not produced in most adult human tissues in the steady state. Present study has revealed that human chondrocytes isolated from healthy adults constitutively express and secrete MMP-13, but that it is rapidly endocytosed and degraded by chondrocytes. Both pro- and activated MMP-13 bind to clusters II and III of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). Domain deletion studies indicated that the hemopexin domain is responsible for this interaction. Binding competition between MMP-13 and ADAMTS-4, -5 or TIMP-3, which also bind to cluster II, further shown that the MMP-13 binding site within cluster II is different from those of ADAMTS-4, -5 or TIMP-3. MMP-13 is therefore co-endocytosed with ADAMTS-5 and TIMP-3 by human chondrocytes. These findings indicate that MMP-13 may play a role on physiological turnover of cartilage extracellular matrix and that LRP1 is a key modulator of extracellular levels of MMP-13 and its internalization is independent of the levels of ADAMTS-4, -5 and TIMP-3.
Highlights
The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that have the capacity to degrade many protein components of the extracellular matrix (ECM)
We estimated approx. 2.0–4.2 × 104 proMMP-13 molecules were secreted by a single chondrocyte in 8 h, but they were rapidly endocytosed through the low-density lipoprotein (LDL) receptor family-mediated endocytosis
We have demonstrated that LRP1 is the major endocytic receptor of Matrix metalloproteinase 13 (MMP-13) in human chondrocytes and that it directly binds to MMP-13, mediating its internalization for subsequent lysosomal degradation
Summary
The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that have the capacity to degrade many protein components of the extracellular matrix (ECM). The enzyme is considered as a major collagenase in the development of osteoarthritis (OA) because of its elevated expression in human OA cartilage and its effective ability to degrade collagen II fibrils [9,23,24]. Further support for this is a study with MMP-13-null mice, whose cartilage was protected from degradation in the surgically induced OA model [25]. Competition studies between MMP-13 and ADAMTS-4, -5 and TIMP-3 further revealed the selectivity of its interaction with LRP1 and the co-endocytosis of MMP-13 with ADAMTS-4, -5 or TIMP-3
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