Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human genetic studies indicate that mutations in type IX and XI collagens result in early-onset osteoarthritis (OA) with a wide spectrum of osteochondrodysplasia. However, a convincing causal chain of events underlying the role of these collagen mutations in the pathogenesis of OA has not been elucidated. Here we show that the expression of a cell surface collagen receptor, discoidin domain receptor 2 (DDR2), is increased in chondrocytes of the articular cartilage of knee joints in mice that develop OA as a result of a heterozygous mutation in type XI collagen. At the same time point, 6 months, we also found increased expression and activity of matrix metalloproteinase 13 (MMP-13) in the mutant mouse knee cartilage. The expression of both DDR2 and MMP-13 was increased in chondrocytes cultured on plates coated with native type II collagen but not on gelatin, and overexpression of DDR2, but not of a truncated form, was found to induce the expression of MMP-13 when chondrocytes were cultured on type II collagen but not on plastic. The DDR2-induced expression of MMP-13 appears to be specific, since we did not observe induction of MMP-1, MMP-3, MMP-8, ADAMTS-4, ADAMTS-5, and IL-1 transcripts in human chondrocytes or Mmp-3, Mmp-8, Adamts-4, Adamts-5, and Il-1 in mouse chondrocytes. Our data suggest that the defect in the cartilage matrix of mice that are heterozygous for a type XI collagen mutation (cho/+) permits activation and up-regulation of DDR2 in chondrocytes. This could be due to increased exposure of chondrocytes to type II collagen as a result of the decreased amount of type XI collagen in the mutant cartilage. The specific induction of MMP-13 by DDR2 in response to its cartilage-specific ligand, type II collagen, may contribute to cartilage damage in hereditary OA.
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PMID:Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. 1550 86

Site-1 protease (S1P) is a proprotein convertase with essential functions in the conversion of precursor proteins to their active form. In earlier studies, we demonstrated that S1P ablation in the chondrocyte lineage results in a drastic reduction in endochondral bone formation. To investigate the mechanistic contribution of S1P to bone development we ablated S1P in the osterix lineage in mice. S1P ablation in this lineage results in osteochondrodysplasia and variable degrees of early postnatal scoliosis. Embryonically, even though Runx2 and osterix expression are normal, S1P ablation results in a delay in vascular invasion and endochondral bone development. Mice appear normal when born, but by day 7 display pronounced dwarfism with fragile bones that exhibit significantly reduced mineral density, mineral apposition rate, bone formation rate and reduced osteoblasts indicating severe osteopenia. Mice suffer from a drastic reduction in bone marrow mesenchymal progenitors as analyzed by colony-forming unit-fibroblast assay. Fluorescence-activated cell sorting analysis of the skeletal mesenchyme harvested from bone marrow and collagenase-digested bone show a drastic reduction in hematopoietic lineage-negative, endothelial-negative, CD105 + skeletal stem cells. Bone marrow mesenchymal progenitors are unable to differentiate into osteoblasts in vitro, with no effect on adipogenic differentiation. Postnatal mice have smaller growth plates with reduced hypertrophic zone. Thus, S1P controls bone development directly by regulating the skeletal progenitor population and their differentiation into osteoblasts.This article has an associated First Person interview with the first author of the paper.
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PMID:Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice. 2943 42