Limb- and tendon-specific <i>Adamtsl2</i> deletion identifies a soft tissue mechanism modulating bone length
Bibliographic record
Abstract
Abstract Disproportionate distal limb shortening is the hallmark of acromelic dysplasias. Among them, geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature, musculoskeletal, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 ( FBN1 ) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and FBN1. Mice lacking ADAMTSL2 die at birth, precluding analysis of postnatal skeletal growth and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. We show that Adamtsl2 is expressed in limb soft tissues, predominantly in tendon. Expression in developing bones is limited to their terminal cell layers that are destined to become articular cartilage and is absent in growth plate cartilage. Adamtsl2 conditional deletion in limb mesenchyme using Prxl -Cre led to an acromelic dysplasia, providing a suitable model for investigation of geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx -Cre, a tendon-specific deleter, also impaired skeletal growth. Specific morphogenetic anomalies were seen in Achilles tendon, along with FBN1 accumulation. Thus, ADAMTSL2, shown here to bind fibrillin microfibrils in vitro, limits fibrillin microfibril formation in tendons and promotes tendon growth. The findings suggest that reduced bone growth in geleophysic dysplasia results from external tethering by short tendons rather than intrinsic growth plate anomalies.
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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) | 0.001 | 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) | 0.003 | 0.001 |
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".