TNF-α Stimulates Matrix Metalloproteinase Expression in Myelodysplastic Syndromes (MDS): Therapeutic Potential for Inhibitors of TNF-α and MMPs.
Bibliographic record
Abstract
Abstract MDS is characterized by ineffective hematopoiesis with increased intramedullary apoptosis which has been correlated in turn with high levels of tumor necrosis factor (TNF)- α. Previously, we showed that TNF-α strongly upregulates the secretion of the matrix metalloproteinases (MMP)-2 and -9 in normal CD34+ cells. Elevated expression of MMPs has been suggested to contribute to cancer progression and leukemic dissemination and MMPs also facilitate the secretion of TNF-α. In this work, we hypothesized that TNF-α-induced MMP production plays a role in the progression of MDS. We therefore examined the effects of recombinant human (rh) TNF-α on the expression and secretion of MMP-2, MMP-9 and membrane type (MT) 1-MMP (known activator of MMP-2), by MNC from MDS patients (using RT-PCR, zymography and Western blotting), as well as the effects of TNF-α on migration of MDS MNC across the reconstituted basement membrane Matrigel. We observed higher mean levels of TNF-α in media conditioned by mononuclear cells (MNC) obtained from 20 patients diagnosed with MDS (RAEB-T (4); RAEB (5), RA (10) and RARS (1)) in comparison to normal controls. We found that (i) MMP-9 is secreted by MDS MNC and this secretion is increased by TNF-α, (ii) MT1-MMP is expressed by the majority of MDS MNC and this expression is upregulated by TNF-α, and (iii) MMP-2 is detectable only in RAEB-T MNC samples and is activated by TNF-α. TNF-α also stimulated the migration of MDS MNC across Matrigel, which was inhibited by the inhibitor of MT1-MMP, epigallocatechin-3-gallate. Moreover, Enbrel (soluble TNF receptor fusion protein), which blocks TNF-α, also inhibited the expression of MT1-MMP and secretion of MMP-9 by MDS MNC as well as their migration across Matrigel. In addition, we observed increased activation of the latent form of MMP-2 in co-cultures of MDS MNC with bone marrow fibroblastic cells. We suggest that in MDS patients, TNF-α stimulates the expression of MMP-9 and MT1-MMP, inducing a highly proteolytic environment in bone marrow which could further increase processing and secretion of endogenous TNF-α. Therefore, we suggest that use of TNF-α inhibitors combined with MMP inhibitors could have therapeutic value in abrogating the progression of MDS.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".