Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to identify bioactive compounds stimulating collagen biosynthesis with potential for osteogenesis imperfecta (OI) type I pharmacological therapy. Of the compounds tested, apigenin glycosides 7-O-glucuronide, 7-O-methylglucuronide and pectolinarin at 30 microM were found to significantly induce collagen type I synthesis in OI fibroblasts without an effect on the overall protein synthesis. None of the compounds displayed any toxicity at that concentration. Secretion of collagen into media was not affected by apigenin 7-O-glucuronide and was slightly increased in cells treated with apigenin 7-O-methylglucuronide and pectolinarin. Furthermore, procollagen secreted by treated cells underwent a more rapid processing into collagen as compared with control untreated cells. In addition, we elucidated the possible mechanism involved in their action. Stimulation of collagen biosynthesis was not due to an increase in cell proliferation, because no differences in DNA content between the compound-treated and untreated cells were observed. Since flavonoids are known as strong inhibitors of metalloproteinases degrading matrix proteins, the increased level of collagen could result from the inhibition of their activity. However, the compounds with a stimulatory effect on collagen synthesis did not influence the activities of collagenase type I, gelatinases A and B, and stromelysin. On the contrary, all compounds stimulated the activity of prolidase which catalyzes the final step of collagen degradation and plays an important role in collagen biosynthesis. Stimulation of collagen synthesis and prolidase activity by apigenin 7-O-glucuronide was accompanied by an increase in IGF-I receptor expression. In contrast, the compounds apigenin 7-O-methylglucuronide and pectolinarin which normalized collagen synthesis in OI cells may exert their effects through beta1-integrin-mediated signaling.
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PMID:Stimulation of collagen biosynthesis by flavonoid glycosides in skin fibroblasts of osteogenesis imperfecta type I and the potential mechanism of their action. 1798 99

The IGF-I receptor (IGF-IR) was identified as a tumor progression factor, but its role in invasion and metastasis has been the subject of some controversy. Previously we reported that in murine lung carcinoma M-27 cells, overexpression of IGF-IR increased the synthesis and activation of matrix metalloproteinase (MMP)-2 via Akt/phosphatidylinositol 3-kinase signaling. In contrast, we show here that in these and other cells, IGF-IR overexpression reduced the constitutive and phorbol 12-myristate 13-acetate (PMA)-inducible expression of three protein kinase C (PKC)-regulated metalloproteinases, MMP-3, MMP-9, and MMP-13, in cultured cells as well as in vivo in sc tumors. To elucidate the underlying mechanism, we analyzed the effect of IGF-IR on PKC expression and activity using wild-type and IGF-IR-overexpressing (M-27(IGFIR)) tumor cells. Our results show that overexpression and activation of IGF-IR reduced PKC-alpha expression, PKC activity, and downstream ERK1/2 signaling, and these effects were reversed in cells expressing kinase (Y(1131,1135,1136)F) or C-terminal (Y(1250/51)F) domain mutants of IGF-IR. This reduction was due to transcriptional down-regulation of PKC-alpha as evidenced by reduced PKC-alpha mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and a blockade of PKC-alpha promoter activation as revealed by a reporter gene assay. Finally, reconstitution of PKC-alpha levels could restore MMP-9 expression levels in these cells. Collectively, these results show that IGF-IR can inhibit PKC-alpha gene transcription and thereby block the synthesis of PMA-regulated MMPs, suggesting that within the same cells, IGF-IR can act as both a positive and negative regulator of MMP expression and function.
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PMID:The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}. 1985 90