Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of PTH and vitamin D on bone are the result of their direct and indirect effects on the functional cells of bone remodeling units and their precursors. These effects are probably modified or controlled by growth factors, cytokines, and PGs generated locally by the process of bone remodeling. Bone remodeling includes resorptive and bone forming phases, each with a longitudinal and a radial component of progression in time and space. Longitudinal resorption is rapid, prolonged and is probably carried out by osteoclasts utilizing hydrogen ions and lysosomal enzymes to remove mineral and organic components of bone in a highly localized and directed fashion. Individual osteoclasts are probably long-lived cells with a nuclear and perhaps a cytoplasmic turnover rate of 8%/day, with replenishment coming from preosteoclasts in the reversal zone. Radial resorption is slower and shorter than longitudinal resorption. It is carried out by reversal phase monocytes whose exact relationship to osteoclasts is not clear. Activated collagenase diffusing from osteogenic cells in the reversal zone could also play a role. The longitudinal rate of bone formation is probably a measure of the rate of proliferation and differentiation of osteogenic cells at the site at which they were activated. The radial rate of bone formation is a measure of how rapidly osteoblasts synthesize and mineralize bone matrix once they reach the resorption surface. PTH and vitamin D have no direct effects on mature osteoclasts. They may have direct stimulatory effects on proliferation and differentiation of osteoclast precursors and their fusion with osteoclasts but this is not clear because the ontogeny of osteoclasts vis a vis monocytes and other phagocytic cells is still not clear. It is likely that their effects to increase osteoclast precursors involve interactions among lymphocytes, monocytes, and hematopoietic stem cells at a distance from bone remodeling units and are mediated by 1,25(OH)2 vitamin D3 induced synthesis of cytokines and colony-stimulating factors. Stimulatory effects of PTH, vitamin D, PGs, and cytokines on osteoclasts are mediated by as yet undefined factors produced by osteoblasts. Osteoblasts stimulated by PTH could also inhibit osteoclasts by synthesizing and releasing PGs. PTH and vitamin D have diverse and often contradictory effects on the functional activity of osteoblast-like cells in vitro that are difficult to interpret because the relationship of these cells to osteoblasts in vivo is not clear.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Morphology and biochemistry of bone remodeling: possible control by vitamin D, parathyroid hormone, and other substances. 305 Feb 72

Until recently, the prevailing view regarding the function of osteoblasts and osteoclasts was to attribute bone formation to the former and bone resorption to the latter. While the capacity of the osteoclast to degrade bone matrix remains unquestioned, there is now provocative evidence indicating that the osteoblast plays a critical role in regulating osteoclast resorptive activity as well as in contributing directly to matrix dissolution. The first of these points follows from observations indicating that the osteoblast (but not the osteoclast) 1) exhibits receptors and/or responses to resorption-promoting agents (including parathyroid hormone and vitamin D), and 2) releases agents capable of stimulating bone resorption. The second point is derived from studies demonstrating that the osteoblast produces neutral collagenase (an enzyme specialized to degrade type I collagen, the principal organic constituent of bone matrix) and an inhibitor capable of blocking collagenase activity. The synthesis of both of these proteins is, in part, regulated by parathyroid hormone and other resorption-stimulating agents and appears to involve control at the transcriptional, translational, and secretory levels. Thus, in both physiologic bone remodeling and modeling, as well as the altered bone turnover associated with some disease states, it is the osteoblast rather than the osteoclast that may hold the key to understanding the mechanism of tissue form and function.
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PMID:New concepts in bone remodeling: an expanding role for the osteoblast. 332 80

A tissue culture technique which permits the simultaneous measurement of collagen synthesis and bone resorption has been developed. Cultured neonatal mouse calvaria undergo resorption when stimulated by a number of agents including parathyroid hormone, vitamin D, and prostaglandin E2. Mouse calvaria are of sufficient size to measure the extent of proline incorporation into collagenase-digestible protein. Four chemically diverse stimulators of bone resorption were tested for their effect on collagen synthesis. For each stimulator tested, the dose-response relationships for the stimulation of resorption and the inhibition of collagen synthesis were found to coincide.
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PMID:Simultaneous measurement of bone resorption and collagen synthesis in neonatal mouse calvaria. 345 44

We have shown that when chondrocytes are isolated by collagenase digestion of hyaline cartilage from growth plate, nasal, and epiphyseal cartilages of bovine fetuses they rapidly elaborate an extracellular matrix in culture. Only growth plate chondrocytes can calcify this matrix as ascertained by incorporation of 45Ca2+, detection of mineral with von Kossa's stain and electron microscopy. There is an extremely close direct correlation between 45Ca2+ incorporation in the first 24 h of culture and the content of the C-propeptide of type II collagen, measured by radioimmunoassay, at the time of isolation and during culture. Moreover, growth plate cells have an increased intracellular content of the C-propeptide per deoxyribonucleic acid and, during culture, per hydroxyproline (as a measure of helical collagen) compared with nasal and epiphyseal chondrocytes. In growth plate chondrocytes 24,25-dihydroxycholecalciferol (24,25-[OH]2D3), but not 1,25-dihydroxycholecalciferol alone, stimulates the net synthesis of the C-propeptide and calcification; proteoglycan net synthesis is unaffected. Together, these metabolites of vitamin D further stimulate C-propeptide net synthesis but do not further increase calcification stimulated by 24,25-(OH)2D3. These observations further demonstrate the close correlation between the C-propeptide of type II collagen and the calcification of cartilage matrix.
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PMID:The calcification of cartilage matrix in chondrocyte culture: studies of the C-propeptide of type II collagen (chondrocalcin). 349 35

Collagen autoimmunity has been suggested as one etiologic mechanism to otosclerosis. Although substantial studies relating this disease to collagen autoimmunity have been reported, a basic understanding of the pathogenic mechanism involved is lacking. Some otosclerosis patients have a high level of antibody to type II collagen. In addition, complement and antibody were deposited in the stapes from otosclerosis patients. Furthermore, the otic capsule and stapes have been found to contain type II collagen by immunohistologic studies and biochemical analysis. Otospongiosis-like lesions have also been produced in rats by immunizing them with type II collagen. This finding led us to postulate a hypothesis of an autoimmunity to type II collagen as an etiopathogenesis of this illness. Our initial hypothesis has been updated to incorporate new findings in the field of cell biology. The role of interleukin 1, osteoclasts, osteoblasts, bone resorption, and other factors such as minor collagens, calcitonin, vitamin D, parathyroid hormone, collagenase, and prostaglandins are incorporated in this updated hypothesis.
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PMID:Enchondral cartilage rests collagen-induced autoimmunity: a possible pathogenetic mechanism of otosclerosis. 350 78

Bone cells isolated from mouse calvariae by a sequential digestion procedure have many osteoblast characteristics: they respond to PTH and prostaglandin E2 by activation of adenylate cyclase but not to calcitonin, they stain for alkaline phosphatase and they make only type I collagen. In confluent monolayer culture, they do not secrete collagenase in appreciable quantities, unless stimulated with resorptive substances such as PTH, prostaglandin E2, 1,25(OH)2 vitamin D-3 and monocyte-conditioned medium. This suggests they play a direct role in bone resorption.
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PMID:Mouse osteoblasts synthesize collagenase in response to bone resorbing agents. 609 72

We compared the effects of four vitamin D metabolites, 1 alpha,25 dihydroxy vitamin D3 (1 alpha,25(OH)2D3), 1 alpha hydroxy vitamin D3 (1 alpha OH D3), 25 hydroxy vitamin D3 (25 OH D3), and 24R,25 dihydroxy vitamin D (24R,25(OH)sD3) on resorption and collagen synthesis in fetal rat bone maintained in organ culture. Resorption was quantitated by measuring the release of previously incorporated 45Ca from long bone shafts of 19-day fetal rats, and collagen synthesis was assessed by measuring the incorporation of 3H-proline into collagenase digestible protein (CDP) in calvaria from 21-day fetal rats. All four compounds stimulated bone resorption and inhibited collagen synthesis, but 1 alpha,25(OH)2D3 was approximately 1000 times more potent in both organ culture systems. Although the differences were small among the other three compounds, the order of potency was 1 alpha OH d3 > 25 OH D3 greater than or equal to 24R,25(OH)2D3. These results suggest that the receptor for 1 alpha 25(OH)2D3 in both bone resorbing and bone forming cells has similar affinities for several vitamin D metabolites.
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PMID:Comparison of the effects of vitamin D metabolites on collagen synthesis and resportion of fetal rat bone in organ culture. 677 30

Renal cells from Vitamin D-deficient and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-repleted chicks were isolated by a collagenase-hyaluronidase procedure. Exclusion of trypan blue and respiratory measurements indicate that the cells were functionally intact and metabolically active. The uptakes of phosphate and alpha-methylglucoside were stimulated markedly by Na+ in the extracellular medium. Phosphate uptake in the presence of Na+ was saturable with respect to phosphate concentration; half-maximal activity was obtained with approximately 0.2 mM. Three hours after 1,25-(OH)2D3 was injected into vitamin D-deficient chicks the Na+-dependent phosphate uptake by the isolated cells had increased about 40%, i.e., 2.00 compared with 1.44 nmol.min-1.mg protein-1. Phosphate uptake in the presence of K+ in the extracellular medium and alpha-methylglucoside uptake in the presence or absence of Na+ were unchanged. In a secondary response found 17 h after 1,25-(OH)2D3 injection, Na+-dependent phosphate uptake decreased. Serum concentrations of phosphorus and calcium were not measurably changed in the 3-h repleted bird, but both levels were increased 17 h after treatment. Administration of phosphate into vitamin D-deficient chicks, so that the serum concentration of phosphorus was raised to that of the 17-h 1,25-(OH)2D3 repleted animal, effected a comparable decrease in phosphate uptake. Serum calcium levels were not altered by this treatment. The actions of parathyroid hormone in stimulating adenylate cyclase and in inhibiting phosphate uptake were notably blunted in the vitamin D-deficient chick. Sensitivity to parathyroid hormone was not restored until several days after 1,25-(OH)2D3 repletion. These findings suggest that the initial response to 1,25-(OH)2D3, to increase renal phosphate uptake, and the secondary response, to decrease phosphate uptake, were by parathyroid hormone-independent processes. The results also indicate that the isolated renal cell represents an excellent model for studying the mechanism by which 1,25-(OH)2D3 regulates phosphate transport in the kidney.
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PMID:Effects of 1,25-(OH)2D3 administered in vivo on phosphate uptake by isolated chick renal cells. 689 66

The question of whether the skeleton metabolizes 25-hydroxycholecalciferol [25(OH)D3] to more-polar products was studied. Calvarial cells were dispersed from 16-day old chicken embryos by using collagenase and then grown in culture in serum-free medium. Confluent cell cultures were incubated with 7 nM 25(OH)[3H]D3 for 2 hr, and the vitamin D metabolites were then extracted. At least four polar metabolites were produced. Based on separation by Sephadex LH-20 chromatography followed by high-pressure liquid chromatography, two of these metabolites were identified as 1,25-dihydroxycholecalciferol [1,25(OH)2D3] and 24,25-dihydroxycholecalciferol [24,25(OH)2D3]. These metabolites were also produced by cultured kidney cells but not by liver, heart muscle, or skin cells isolated from the same embryos. The specific activities of the calvarial 1- and 24-hydroxylases were similar in magnitude to those in isolated kidney cells. The specific activity of the calvarial 25(OH)D3:1-hydroxylase was inhibited by an 8-hr preincubation with 1,25(OH)2D3, whereas the 24-hydroxylase was enhanced. It is concluded that (i) vitamin D metabolism by isolated cells is organ-specific, (ii) calvarial cells produce active metabolites of vitamin D in significant amounts, (iii) vitamin D metabolism by calvarial cells is regulated by 1,25(OH)2D3, and (iv) locally produced, active metabolites could act locally, thereby adding a new dimension to the regulation of mineral metabolism by vitamin D metabolites.
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PMID:In vitro synthesis of 1 alpha,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol by isolated calvarial cells. 693 5

Matrix remodeling plays a prominent role in growth plate calcification. Since interleukin-1 (IL-1) has been implicated in stimulating proteinase production and inhibiting matrix synthesis in articular cartilage, we examined whether IL-1 was present in growth plate and whether the vitamin D metabolites, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3; 1,25) and 24,25(OH)2D3 (24,25), regulate the level of IL-1 found in this tissue. Sprague-Dawley rats were placed on normal (Normal rats) or rachitogenic diet (-VDP rats). The -VDP rats were either left untreated, injected 24 h prior to euthanasia with 24,25 (-VDP+24,25 rats) or 1,25 (-VDP+1,25 rats), or were given ergocalciferol (Ergo rats) orally, 48 h prior to euthanasia. Growth plates were harvested and extracted in buffer containing 1 M guanidine. IL-1 activity was measured by adding authentic cytokine or growth plate extracts to cultures of lapine articular cartilage and assaying release of glycosaminoglycans (GAGs) and changes in collagenase and neutral metalloproteinase activity. Neutralization of activity in the extracts was performed using polyclonal antisera to IL-1alpha or IL-1beta. An ELISA was used to determine levels of IL-1alpha and beta in the extracts. All extracts contained IL-1alpha and beta, as determined by ELISA. Levels of IL-1beta, but not IL-1alpha, were affected by the vitamin D status of the animal. Extracts from -VDP+24,25 animals contained significantly more IL-1beta than any of the other treatment groups, with the level found in these animals being 3-fold higher than normal and 2-fold higher than -VDP. Extracts were also tested in the bioassay to determine the level of active cytokine present. All growth plate extracts contained activity which altered GAG and proteinase release by lapine articular cartilage. Extracts from -VDP-, -VDP+1,25-, and -VDP+Ergo-treated rats stimulated a 40% increase in glycosaminoglycan release compared with extracts from normal rats. In contrast, extracts from -VDP+24,25-treated rats stimulated a 300% increase in glycosaminoglycan release. Both collagenase and neutral metalloproteinase activity of lapine cartilage were increased after incubation with the growth plate extracts. Collagenase activity was significantly increased 8- to 13-fold by the addition of extracts from -VDP-, -VDP+24,25-, or -VDP+1,25-treated animals. Neutral metalloproteinase activity was similarly increased by 4- to 10-fold. To characterize this activity further, growth plate extracts were incubated with neutralizing antibody to IL-1alpha or beta prior to addition to the lapine articular cartilage cultures. When antibodies were used separately, only partial inhibition was observed; incubation with both antibodies blocked 25% of the glycosaminoglycan release observed without antibody and greater than 80% of the enzyme activity released by the articular cartilage cultures. The results of this study show that growth plate cartilage contains both IL-1alpha and beta and indicate that vitamin D regulates the level of IL-1 in this tissue.
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PMID:Interleukin-1alpha and beta in growth plate cartilage are regulated by vitamin D metabolites in vivo. 933 16


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