Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model?
Notice bibliographique
Résumé
BACKGROUND: Sclerostin is a secreted glycoprotein that inhibits the intracellular Wnt signaling pathway, which, when inactivated, stimulates bone formation. This has been seen in fracture studies, which have shown larger and stronger calluses with accelerated fracture healing in sclerostin knockout and sclerostin antibody injection models. However, the effects of these two mechanisms have not been compared in the context of fracture healing. QUESTIONS/PURPOSES: We sought to determine the degree to which sclerostin inhibition (Scl-Ab injection) and complete sclerostin depletion inhibit fracture healing in a mouse model as evaluated by (1) morphometric trabecular bone measures at the fracture site, and (2) fracture site structural strength. METHODS: Ten-week-old male sclerostin knockout (n = 20) and wild type (n = 40) mice underwent insertion of a tibial intramedullary pin after which a midshaft tibial osteotomy was performed. The mice were divided in three groups: sclerostin knockout (n = 20), wild type with sclerostin antibody injection (intravenous dose of 100 mg/kg weekly) (n = 20), and wild type with saline injection (n = 20). The mice for each group where subdivided and euthanized at 14, 21, 28, and 35 days after surgery, at which time the fractured tibias were assessed with microCT (to assess morphometric trabecular bone measures: bone volume to total volume (BV/TV), trabecular thickness, trabecular number, and structural model index at the fracture site. Biomechanical testing in the form of three-point bending also was done to assess fracture site structural strength. A difference greater than 3.7% in our primary outcome (BV/TV) would be required to detect a difference between groups with a power of 80%, as per our power analysis. RESULTS: The wild type with sclerostin antibody and the sclerostin knockout groups showed increased trabecular BV/TV at the fracture site compared with the wild type group with saline at all times, however no difference was seen between the treatment groups with the numbers available, except at 28 days postoperatively when the sclerostin knockout group showed greater BV/TV than the wild type sclerostin antibody group (47.0 ± 3.5 vs 40.1 ± 2.1; p < 0.05). On biomechanical testing the wild type sclerostin antibody showed increased stiffness at Days 14 and 28 compared with the wild type with saline group (70.9 ± 6.4 vs 14.8 ± 8.1; p = 0.001), (106.8 ± 24.3 vs 74.9 ± 16.0; p = 0.004); respectively. However, with the numbers available, no differences were detected between the wild type with sclerostin antibody and the sclerostin knockout groups in terms of whole-bone structural strength. CONCLUSIONS: Sclerostin antibody injections showed promising results, which were not different with the numbers available, from results achieved with complete depletion of sclerostin, especially at earlier stages of the healing process, and therefore completed the healing process at an earlier time. CLINICAL RELEVANCE: Sclerostin antibody injections appear to enhance fracture healing to a degree that is not different than complete sclerostin depletion, but larger animal studies are required to assess the accurate dosage and timing of administration in the fracture healing process to further evaluate its potential clinical utility to enhance fracture healing.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».