Targeting <scp>TGF</scp>‐β signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica
Bibliographic record
Abstract
Abstract GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF‐β signaling. In this study, we investigated the role of TGF‐β‐signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of Gorab Prx1 conditional knockouts with the TGF‐β neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF‐β overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF‐β dysregulation was not a cell‐intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF‐β signaling caused elevated Nox4 expression in Gorab Prx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN‐mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating Gorab Prx1 mutants with the antioxidant N‐acetylcysteine ameliorated the osteoporosis phenotype. TGF‐β induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the Gorab Prx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a , thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF‐β‐Nox4‐senescence axis and therapeutic strategies for GO.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".