Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional periprosthetic bone resorption plays an important role of prosthesis loosening. In order to study the possible mechanisms of loosening, we investigated the presence of matrix proteolytic enzymes in the periprosthetic tissue by immunohistochemical technique in 72 patients undergoing revision operation of loosened joint prosthesis, including 22 males and 50 females and aged from 19 to 88 years (mean, 61.7 years). Thirty-nine patients had a loosened hip prosthesis (18 males and 21 females) whereas 33 patients had a loosened knee prosthesis (4 males and 29 females). Tissue specimens collected during revision surgery underwent thin slide sections and H & E staining, and were observed under light microscopy and polarized-light microscopy. The results showed many macrophages, histiocytes, fibroblasts, as well as many phagocytosed metal debris and polyethylene debris in the periprosthetic tissues, suggesting an active bone resorption. Furthermore, we used immunohistochemical techniques to detect the distribution of matrix proteolytic enzymes in periprosthetic tissue, including lysosome enzymes (cathepsin B, cathepsin D and cathepsin G), and matrix metalloproteinase (MMPs, MMP-1, MMP-2, MMP-3). The immunostaining were classified as strong positivity, > 70% positive cells; moderate positivity, 20-70% positive cells; weak/negative, < 20% positive cells. The results showed that cathepsin B, cathepsin D and cathepsin G were found in most fibroblasts and macrophage-like cells, including multinuclear giant cells and epithelioid cells. MMPs were found in most fibroblasts and macrophage-like cells, as well as a scant amount in the extracellular matrix. These enzymes were also found in or around blood vessels, the endothelial cells in the richly vascularized tissue. All negative controls showed no staining. The results of immunoreactive staining ranged from 61.1% to 68.1% of strong to moderate positivity. Since these enzymes were related to the degradation of matrix protein, they may be related to the periprosthetic bone resorption. The further clinical significance needs further investigation.
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PMID:Immunohistochemical analysis of matrix proteolytic enzymes in the periprosthetic tissue in the patients with loosening prostheses. 960 17

Interactions of stromal and tumor cells with the extracellular matrix may regulate expression of proteases including the lysosomal proteases cathepsins B and D. In the present study, we determined whether the expression of these two proteases in human breast fibroblasts was modulated by interactions with the extracellular matrix component, collagen I. Breast fibroblasts were isolated from non-malignant breast tissue as well as from tissue surrounding malignant human breast tumors. Growth of these fibroblasts on collagen I gels affected cell morphology, but not the intracellular localization of vesicles staining for cathepsin B or D. Cathepsins B and D levels (mRNA or intracellular protein) were not affected in fibroblasts growing on collagen I gels or plastic, nor was cathepsin D secreted from these cells. In contrast, protein expression and secretion of cathepsin B, primarily procathepsin B, was induced by growth on collagen I gels. The induced secretion appeared to be mediated by integrins binding to collagen I, as inhibitory antibodies against alpha(1), alpha(2), and beta(1) integrin subunits prevented procathepsin B secretion from fibroblasts grown on collagen. In addition, procathepsin B secretion was induced when cells were plated on beta(1) integrin antibodies. To our knowledge, this is the first examination of cathepsin B and D expression and localization in human breast fibroblasts and their regulation by a matrix protein. Secretion of the cysteine protease procathepsin B from breast fibroblasts may have physiological and pathological consequences, as proteases are required for normal development and for lactation of the mammary gland, yet can also initiate and accelerate the progression of breast cancer.
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PMID:Interaction of human breast fibroblasts with collagen I increases secretion of procathepsin B. 1207 42

The effect of osteocalcin (OC), an extracellular bone matrix protein, on bone healing around hydroxyapatite/collagen composites was investigated. Cylindrical nanocrystalline hydroxyapatite implants of 2.5-mm diameter containing 2.5% biomimetically mineralized collagen type I were inserted press-fit into the tibial head of adult Wistar rats. To one implant group, 10 mug/g OC was added. Six specimens per group were analyzed at 2, 7, 14, 28, and 56 days. After 14 days, newly formed woven bone had reached the implant surface of the OC implants whereas a broad fibrous interface could still be observed around controls. Woven bone was formed directly around both implant groups after 28 days and had been replaced partially by lamellar bone around the OC implants only. No significant differences in total bone contact were seen between both groups after 56 days. The higher number of phagocytosing cells and osteoclasts characterized immunohistochemically with ED1, cathepsin D, and tartate-resistant alkaline phosphatase around the OC implants at the early stages of bone healing suggests an earlier onset of bone remodeling. The earlier and increased expression of bone-specific matrix proteins and multifunctional adhesion proteins (osteopontin, bone sialoprotein, CD44) at the interface around the OC implants indicates that OC may accelerate bone formation and regeneration. This study supports the observations from in vitro studies that OC activates both osteoclasts and osteoblasts during early bone formation.
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PMID:Osteocalcin enhances bone remodeling around hydroxyapatite/collagen composites. 1580 Aug 55

Increased expression of several osteoblastic proteases and MEPE (a bone matrix protein) occurs in X-linked hypophosphatemic rickets (hyp). This is associated with an increased release of a protease-resistant MEPE peptide (ASARM peptide), a potent inhibitor of mineralization. Cathepsin B cleaves MEPE releasing ASARM peptide and hyp osteoblast/osteocyte cells hypersecrete cathepsin D, an activator of cathepsin B. Our aims were to determine whether cathepsin inhibitors correct the mineralization defect in vivo and whether hyp-bone ASARM peptide levels are reduced after protease treatment. Normal littermates and hyp mice (n = 6) were injected intraperitoneally once a day for 4 weeks with pepstatin, CAO74 or vehicle. Animals were then sacrificed and bones plus serum removed for comprehensive analysis. All hyp mice groups (treated and untreated) remained hypophosphatemic with serum 1,25 vitamin D3 inappropriately normal. Serum PTH was significantly elevated in all hyp mice groups relative to normal mice (P = 0.0017). Untreated hyp mice had six-fold elevated levels of serum alkaline-phosphatase and two-fold elevated levels of ASARM peptides relative to normal mice (P < 0.001). In contrast, serum alkaline phosphatase and serum ASARM peptides were significantly reduced (normalized) in hyp mice treated with CA074 or pepstatin. Serum FGF23 levels remained high in all hyp animal groups (P < 0.0001). Hyp mice treated with protease inhibitors showed dramatic reductions in unmineralized osteoid (femurs) compared to control hyp mice (Goldner staining). Also, hyp animals treated with protease inhibitors showed marked and significant improvements in growth plate width (42%), osteoid thickness (40%) and cortical area (40%) (P < 0.002). The mineralization apposition rate, bone formation rate and mineralization surface were normalized by protease-treatment. High-resolution pQCT mineral histomorphometry measurements and uCT also confirmed a marked mineralization improvement. Finally, the growth plate and cortical bone of hyp femurs contained a massive accumulation of osteoblast-derived ASARM peptide(s) that was reduced in hyp animals treated with CA074 or pepstatin. This study confirms in vivo administration of cathepsin inhibitors improves bone mineralization in hyp mice. This may be due to a protease inhibitor mediated decrease in proteolytic degradation of the extracellular matrix and a reduced release of ASARM peptides (potent mineralization inhibitors).
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PMID:Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin. 1676 7

The influence of an intensive exercise regime on cathepsin D and MMP-9 activity in hind limb muscles was investigated. We hypothesized that high-intensity exercise would increase the number of these proteins, indicating their involvement in the pathogenesis of exercise-induced muscle injury. Muscle fibers from the gastrocnemius and soleus were used from young (6-mo-old) female rats (n = 6) who completed 10 consecutive days of treadmill running at high intensity (34 m min(-1) gradually up to 40 min per day), compared with nonrunning, age and sex-matched rats (n = 6). After a high-intensity exercise regime, cathepsin D activity significantly increased in the gastrocnemius (from 6.6 x 10(-3) to 10.7 x 10(-3) or 61% nM tyrosine x mg-1 protein x min-1) and the soleus (from 5.9 x 10(-3) to 8.9 x 10(-3) or 66%). The activity level of mRNA MMP-9, expressed as ng mg(-1) protein, increased in both muscles subjected to intensity running. The results of this study suggest that high-intensity running results in an elevation in the activity of lysosomal enzymes involved in matrix protein degradation.
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PMID:Cathepsin D and MMP-9 activity increase following a high intensity exercise in hind limb muscles of young rats. 1756 48