Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children
Bibliographic record
Abstract
Deficiency of matrix metalloproteinase 2 (MMP-2) causes a complex syndrome characterized by multicentric osteolysis, nodulosis and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism. MMP-2 deficient (Mmp2-/-) mice are a model for this rare multisystem pediatric syndrome but their phenotype remains incompletely characterized. Here, we extend the phenotypic characterization of MMP-2 deficiency by comparing the levels of cytokines and chemokines, soluble cytokine receptors, angiogenesis factors, bone development factors, apolipoproteins and hormones in mice and humans. Initial screening was performed on an eight-year-old male presenting a previously unreported deletion mutation c1294delC (Arg432fs) in the MMP2 gene and diagnosed with MONA. Of eighty-one serum biomolecules analyzed, eleven were upregulated (>4-fold), two were downregulated (>4-fold) and sixty-eight remained unchanged, compared to unaffected controls. Specifically, Eotaxin, GM-CSF, M-CSF, GRO-α, MDC, IL-1β, IL-7, IL-12p40, MIP-1α, MIP-1β and MIG were upregulated and EGF and ACTH were downregulated in this patient. Subsequent analysis of five additional MMP-2 deficient patients confirmed the upregulation in Eotaxin, IL-7, IL-12p40 and MIP-1α, and the downregulation in EGF. To establish whether these alterations are bona fide phenotypic traits of MMP-2 deficiency, we further studied Mmp2-/- mice. Among 32 cytokines measured in plasma of Mmp2-/- mice, the cytokines Eotaxin, IL-1β, MIP-1α and MIG were commonly upregulated in mice as well as patients with MMP-2 deficiency. Moreover, bioactive cortisol (a factor that exacerbates osteoporosis) was also elevated in MMP-2 deficient mice and patients. Among the factors we have identified to be dysregulated in MMP-2 deficiency many are osteoclastogenic and could potentially contribute to bone disorder in MONA. These new molecular phenotypic traits merit being targeted in future research aimed at understanding the pathological mechanisms elicited by MMP-2 deficiency in children.
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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 | 0.001 | 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".