Role of Fibronectin in Postnatal Skeletal Development
Bibliographic record
Abstract
Abstract Fibronectin (FN) is a ubiquitous matrix glycoprotein essential for the physiological development of various tissues. Mutations in FN cause a form of skeletal dysplasia, emphasizing the importance of FN in cartilage and bone development. However, the relevance and functional role of FN during skeletal development remains elusive. We employed conditional knockout mouse models for the cellular FN isoform in cartilage (cFNKO), the plasma FN isoform in hepatocytes (pFNKO), and a double knockout (FNdKO) to determine the relevance of these two principal FN isoforms in postnatal skeletal development spanning from P1 to 2 months of age. We identified a unique topological FN deposition pattern in the mouse limb with prominent levels at the resting and hypertrophic chondrocyte zones and in the trabecular bone. Circulating pFN did not enter the growth plate and was limited to the primary ossification center, whereas cartilage-specific cFN was detected as the major isoform in epiphyseal cartilage. Deletion of either one of the isoforms in single knockouts (cFNKO or pFNKO) only led to subtle changes in some of the analyzed parameters. Complete ablation of both cFN in the growth plate and circulating pFN in plasma resulted in significantly reduced postnatal body weight, body length, and bone length in the FNdKO mice. Assessment of the FNdKO adult bone microarchitecture using micro-CT revealed significantly reduced trabecular bone volume, trabecular network, bone mineral density, and increased bone marrow adiposity. Analysis of chondrogenesis in FNdKO mice showed changes in the proliferating and hypertrophic growth plate zones, consistent alterations in chondrogenic markers such as collagen type II and type X, reduced apoptosis of hypertrophic chondrocytes, and downregulation of bone formation markers. FNdKO mice also displayed decreased levels of transforming growth factor-β1 (TGFβ1) and downstream phospho-AKT levels, which are critical regulators of chondrogenesis and bone formation. In conclusion, the data demonstrate that FN is essential for proper chondrogenesis and postnatal bone development. Simultaneous deletion of both FN isoforms in the developing cartilage leads to critical TGFβ-mediated alterations in chondrogenic differentiation, resulting in bone and skeletal defects. Significance/Highlights FN is highly expressed during mouse limb development with increased deposition in resting and hypertrophic chondrocyte zones and the primary ossification center. Cartilage-specific cFN and circulating pFN are distinctly distributed during embryonic and postnatal bone development, with chondrocyte-specific cFN present in the growth plate and pFN limited to trabecular bone and the bone marrow. Deletion of both cFN and pFN leads to reduced bone growth during early postnatal development. Deletion of cFN and pFN leads to reduced trabecular bone formation, bone mineralization, and increased bone marrow adiposity in 2-month adult mice. Absence of both FN isoforms in the FNdKO mouse model leads to altered chondrogenesis and reduced bone formation. FN regulates chondrogenesis via TGFβ-mediated phospho-AKT signaling.
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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".