Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis

Abstract

These results suggest a mechanism whereby impaired receptor-mediated removal of collagenase-3 in OA chondrocytes may lead to enhanced local degradation of the cartilage matrix. This work also implicates an LRP family member in endocytotic receptor-mediated collagenase-3 processing and suggests a novel therapeutic target for OA.

Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

“…Lowering the concentration of ADAMTS-4 clearly demonstrated that 3-5-fold less GAG is released from live cartilage compared with dead cartilage. Subtraction of the basal levels of GAG release from live and dead cartilage also unmasked the significantly reduced GAG release in live cartilage incubated with MMP-13 (data not shown), which has previously shown to be endocytosed by chondrocytes via LRP1 (28,29). LRP1-mediated endocytosis is, therefore, a newly discovered mechanism for regulating ADAMTS-4 activity in cartilage.…”

“…This led us to discover that ADAMTS-5 is endocytosed via LRP1 by viable chondrocytes. In those studies we observed no significant differences in aggrecan degradation between live and dead cartilage when ADAMTS-4, MMP-1, or MMP-13 was added (17), although MMP-13 has been reported to be endocytosed by chondrocytes via LRP1 (28,29). However, the concentrations of ADAMTS-4 and MMP-13 used in those studies were 10-fold higher than that of ADAMTS-5, as ADAMTS-5 is the most active aggrecanase (10,11).…”

“…7 The ablation of the LRP1 gene in mice is embryonically lethal (26), but tissue specific deletion of the LRP1 gene has demonstrated that it protects the vasculature and controls ␤-amyloid precursor protein trafficking, lipid metabolism in adipocytes, and macrophage biology (27). In cartilage, LRP1 can endocytose MMP-13 (28,29) and tissue inhibitor of metalloproteinases (TIMP-3), which inhibits collagenases and aggrecanases (30,31). LRP1 interacts with frizzled-1 and down-regulates the canonical Wnt-␤-catenin signaling pathway (32).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Internalization of MMP-13 is mediated by a 170-kDa receptor both in rodent cells and in human chondrocytes (Walling et al, 2003). As mentioned above, MMP-13 is expressed in RA, an arthritic disease characterized by chronic inflammation and cartilage destruction.…”

Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers

“…In studies of patients with juvenile idiopathic arthritis, MMP-13 was also undetectable in serum and synovial fluid (26), while other authors have detected MMP-13 in the serum of patients with osteoarthritis (27,28). It has been suggested that levels of MMP-13 in RA patients may be low due to active removal and degradation by chondrocytes and synoviocytes via a specific surface MMP-13 receptor (29)(30)(31).…”