The roles of cellular Factor XIII-A in osteoblasts
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Bibliographic record
Abstract
Transglutaminases (TG) enzymes are expressed in wide variety of tissues and found in different cellular compartments, where they participate in various biological functions ranging from tissue stabilization to cell signaling. We have shown previously that MC3T3-E1/C14 osteoblasts express both transglutaminase 2 and Factor XIII-A (FXIII-A), the latter one appearing to be active as a transglutaminase during osteoblast differentiation. While data exists on the roles of FXIII-A as an extracellular stabilizer of matrix molecules in blood clots, during wound healing and during bone formation in vitro, the potential cellular functions of FXIII-A are not well understood. This thesis focuses on investigating the role of FXIII-A in osteoblasts and reports two new potential functions for FXIII-A. First contribution shows that in osteoblast FXIII-A activity targets the detyrosinated tubulin (Glu-tubulin) and promotes the formation of a high 150 kDa Glu-tubulin which is more stable in osteoblasts than the monomer form. This crosslinked Glu-tubulin is also membrane associated and found on the cell surface of osteoblasts where its presence is linked to secretion and deposition of extracellular matrix during osteoblast differentiation. We show that only α-tubulin, which gives rise to Glu-tubulin, is a TG substrate in vitro activity assay. The data in this thesis also shows that previously observed FXIII-A patches represent a pool of FXIII-A in caveolae, which are specialized membrane invaginations that have long been implicated in vesicular transport and signal transduction. We show FXIII-A co-localizes with caveolin-1 on the inner leaflet of plasma membrane in differentiating osteoblasts. Despite the presence of FXIII-A, caveolae had no detectable TG activity suggesting that FXIII-A may have a non-crosslinking function in caveolae. An irreversible TG inhibitor, NC9, which is capable of also altering TG enzyme conformation, displaced FXIII-A from caveolae which is linked to increased c-Src activation and increased caveolin-1 phosphorylation and homo-oligomerization. This suggests that cellular FXIII-A in osteoblasts has a role on regulating c-Src signaling. In summary, results in this thesis suggest that FXIII-A has both crosslinking and non-catalytic functions which regulate extracellular matrix accumulation and signaling pathways in osteoblasts, respectively.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.003 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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 it