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Biomedical subjects

M A Moses

Publications and source records attributed to M A Moses.

51 records · Page 3Linked to original sources
PubMed1994

Production of matrix metalloproteinases and a metalloproteinase inhibitor by swarm rat chondrosarcoma.

Chondrosarcoma was found to produce a heat-labile collagenase and a heat-stable collagenase inhibitor. Unlike its cartilage counterpart, the inhibitory activity in chondrosarcoma could only be detected after heat-treatment. Western blot analysis of chondrosarcoma-derived inhibitor showed that this inhibitor cross-reacted with a polyclonal antibody raised against purified cartilage-derived collagenase inhibitor (1) at a M.W. of about 33 kDa. In addition to the collagenase activity, which appears to be matrix metalloproteinase I (MMP-1), chondrosarcoma extracts were shown to contain four active gelatinase species which migrate at a molecular weight consistent with that reported for MMP-2 (72 kDa gelatinase, Type IV gelatinase) (2) and three active enzyme species which migrate at a molecular weight consistent with that reported for MMP-9 (92 kDa gelatinase, Type IV gelatinase) (3,4). In contrast, normal cartilage contained only two active and one latent form of MMP-2 in significantly lower amounts than in chondrosarcoma. In the case of MMP-9, the same three species were present in normal cartilage and in chondrosarcoma, but in lower amounts in the normal tissue. These results suggest that chondrosarcoma might develop in vivo because the inherent proteolytic balance between the protease(s) and its endogenous inhibitor(s) is shifted in favor of the enzyme.

Animals↗
PubMed1994

Heparinase inhibits neovascularization.

Neovascularization is associated with the regulation of tissue development, wound healing, and tumor metastasis. A number of studies have focused on the role of heparin-like molecules in neovascularization; however, little is known about the role of heparin-degrading enzymes in neovascularization. We report here that the heparin-degrading enzymes, heparinases I and III, but not heparinase II, inhibited both neovascularization in vivo and proliferation of capillary endothelial cells mediated by basic fibroblast growth factor in vitro. We suggest that the role of heparinases in inhibition of neovascularization is through depletion of heparan sulfate receptors that are critical for growth factor-mediated endothelial cell proliferation and hence neovascularization. The differences in the effects of the three heparinases on neovascularization could be due to different substrate specificities for the enzymes, influencing the availability of specific heparin fragments that modulate heparin-binding cytokines involved in angiogenesis.

Allantois↗
PubMed1994

Purification and characterization of two collagenase inhibitors from mouse sarcoma 180 conditioned medium.

We have previously shown that mouse sarcoma 180 cells produce vascular endothelial growth factor [VEGF; Rosenthal et al., 1990, Growth Factors, 4: 53-59], an endothelial mitogen that stimulates angiogenesis. Recent reports have implicated metalloproteinases and their inhibitors in the regulation of vascular morphogenesis, tumor invasion, and metastasis. We report here that mouse sarcoma 180 cells produce two collagenase inhibitors. These inhibitors were purified by heparin-Sepharose affinity chromatography, gel filtration, and C4 reverse phase h.p.l.c. Analytical gel electrophoresis of the purified inhibitors (MS-22 and MS-31) revealed molecular masses of 22,000 and 31,000 Da under reducing conditions, and 20,000 and 30,000 Da under nonreducing conditions, respectively. The NH2-terminal amino acid sequence of MS-22 was identical to that of tissue inhibitor of metalloproteinases type 2 (TIMP-2) produced by human melanoma cells [Stetler-Stevenson et al., 1989, J. Biol. Chem. 264: 17374-17378) over the first 30 amino acids. The NH2-terminal amino acid sequence of MS-31 was identical to that of murine TIMP-1 [Gewert et al., 1989, EMBO J 6:651-657]. Statistical analysis of the amino acid composition data of these two mouse sarcoma 180-derived collagenase inhibitors confirms the identification of MS-22 as TIMP-2 and MS-31 as TIMP-1.

Amino Acid Sequence↗
PubMed1992

Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes.

An inhibitor of neovascularization from the conditioned media of scapular chondrocytes established and maintained in serum-free culture has been isolated and characterized. To determine whether this chondrocyte-derived inhibitor (ChDI) was capable of inhibiting neovascularization in vivo, this protein was assayed in the chick chorioallantoic membrane assay. ChDI was a potent inhibitor of angiogenesis in vivo (4 micrograms = 87% avascular zones). This inhibitor is also an inhibitor of fibroblast growth factor-stimulated capillary endothelial cell (EC) proliferation and migration, as well as being an inhibitor of mammalian collagenase. ChDI significantly suppressed capillary EC proliferation in a dose-dependent, reversible manner with an IC50 (the inhibitory concentration at which 50% inhibition is achieved) of 2.025 micrograms/ml. Inhibition by ChDI of growth factor-stimulated capillary EC migration was also observed using a modified Boyden chamber assay (IC50 = 255 ng/ml). SDS-PAGE analysis followed by silver staining of ChDI purified to apparent homogeneity revealed a single band having an M(r) of 35,550. Gel elution experiments demonstrated that only protein eluting at this molecular weight was anti-angiogenic. These studies are the first demonstration that chondrocytes in culture can produce a highly enriched, potent inhibitor of neovascularization which also inhibits collagenase.

Allantois↗
PubMed1991

A metalloproteinase inhibitor as an inhibitor of neovascularization.

Metalloproteinases and their endogenous inhibitors are key components of an enzyme system which is important in a number of fundamental biochemical and cellular processes. Our recent work has focused on the role of a particular metalloproteinase, collagenase, and the role of an endogenous inhibitor of this enzyme in the control of neovascularization. The proteolytic degradation of extracellular matrix components by capillary endothelial cells (EC) has been shown to be one of the key prerequisites of the angiogenic process. As part of a study of the effect(s) of the inhibition of collagenase on neovascularization, we have recently reported the purification, characterization and partial NH2-terminal sequence of a cartilage-derived inhibitor (CDI) of angiogenesis in vivo and in vitro. Evidence is presented which suggests that one means of controlling deregulated vascular growth characteristic of a number of "angiogenic diseases" may be at the level of the control of metalloproteinase activity.

Amino Acid Sequence↗
PubMed1991

Inhibitors of angiogenesis.

Angiogenesis, the formation of new capillaries, is essential to a number of important physiological events, both normal and pathological. Recently, increased attention has focused on the purification and characterization of inhibitors of this process, because of the potential therapeutic value of angiogenesis inhibitors in controlling such "angiogenic diseases" as proliferative retinopathy, solid tumors, rheumatoid arthritis, and neovascular glaucoma. We review the process of neovascularization and the assays that have been developed to study its inhibition in vivo and in vitro. We also discuss the properties of different angiogenesis inhibitors and examine the mechanisms by which such inhibitors could potentially intervene in the process of neovascularization.

Animals↗
PubMed1990

Identification of an inhibitor of neovascularization from cartilage.

Certain tissues such as cartilage are resistant to vascular invasion, yet no single tissue-derived molecule that can inhibit angiogenesis has been reported. A protein derived from cartilage was purified that inhibits angiogenesis in vivo and capillary endothelial cell proliferation and migration in vitro in three separate bioassays. This protein is also an inhibitor of mammalian collagenase. These findings may help elucidate the mechanisms by which neovascularization is controlled in both normal and pathological states.

Adrenal Cortex↗
PubMed1989

Distribution of [3H]MK801 binding in the normal aged human hippocampus.

The distribution of NMDA receptors in the normal human hippocampus has been investigated using the non-competitive channel blocking agent, MK801. The pattern of specific [3H]MK801 binding was broadly similar to that previously described for agonist binding although differences included equal densities in h1 and h2 regions where binding was mainly confined to the pyramidal layer and stratum radiatum.

Aged↗
PubMed1987

Control of low Km cyclic adenosine 3',5'-monophosphate-phosphodiesterase in prostate and heart of adult and aged rats.

The activity of low Km cAMP-phosphodiesterase (PDE) was determined in extracts of prostate and heart of adult (10-12 months old) and aged (32-35 months old) Sprague-Dawley rats; the enzyme's response to endogenous inhibitors extracted from the two organs was analyzed by kinetic studies. Different mechanisms of inhibition, non-competitive in prostate and competitive in heart extracts, indicate organ-specificity of the inhibitor. The decreased PDE activity in organ extracts of aged rats and its continued sensitivity to the endogenous inhibitor suggest an age-associated impairment of the tissues' ability to terminate cAMP-mediated signals.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

The regulation of delta-opiate receptor density on 108CC15 neuroblastoma X glioma hybrid cells.

The effect of exogenous substances on the expression of opiate receptors on 108CC15 neuroblastoma X glioma hybrid cells has been studied. Cell differentiation by culture in the presence of N6-O2-dibutyryl adenosine 3',5'-cyclic monophosphate induced a three fold increase in opiate receptor density. When the cells were grown in the presence of 10(-5) M morphine hydrochloride for up to 23 days, opiate receptor densities were reduced by only 30% when compared with matched controls. Culture in the presence of 10(-7) M D-Ala2-D-Leu5-enkephalin produced opiate receptor down regulation of 73% compared to controls after only 4 h of treatment. The down regulation process could be inhibited by continued exposure to D-Ala2 D-Leu5-enkephalin at concentrations greater than 4 nM; below this concentration down regulation was rapid and irreversible. A model to explain these observations is described.

Animals↗
PubMed1983

Down regulation of opiate receptors on 108CC15 hybrid cells is inhibited by receptor occupancy.

This study reports on the molecular mechanism of delta-opiate receptor down regulation on 108CC15 neuroblastoma X glioma hybrid cells. The down regulation induced by culture in the presence of 10(-5) M 2-D-Ala, 5-D-Leu-enkephalin (DADLE) can be prevented by continued exposure to ligand concentrations greater than 4 nM, the Kd of the binding site. Below this concentration, down regulation is a rapid and irreversible process. It is deduced that the internalization process in this cell line is initiated when unoccupied receptor dimers are present. These results have important implications for down regulation studies using cultured cell lines and studies of receptor regulation in vivo after chronic treatment with neuroactive drugs.

Animals↗
PubMedDate not supplied

A cartilage-derived inhibitor of neovascularization and metalloproteinases.

It is now recognized that persistent neovascularization is a characteristic feature of a number of serious diseases including rheumatoid arthritis. In this case, deregulated capillary growth is a prominent event in the development of the rheumatoid synovial pannus. Cartilage is a normally avascular tissue and it has been suggested that a decrease or depletion of inhibitors of angiogenesis might be responsible, at least in part, for the vulnerability of cartilage to synovial attack. Our laboratory has recently purified and characterized a potent inhibitor of angiogenesis in vivo and in vitro from cartilage and from the conditioned media of chondrocytes. Importantly, this protein is also an inhibitor of mammalian collagenase.

Animals↗