Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model.
biology of tendon
biomechanics of tendon
growth factors/healing enhancement
rotator cuff
shoulder
Journal
The American journal of sports medicine
ISSN: 1552-3365
Titre abrégé: Am J Sports Med
Pays: United States
ID NLM: 7609541
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
pubmed:
29
1
2021
medline:
28
4
2021
entrez:
28
1
2021
Statut:
ppublish
Résumé
More than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway. To evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair. Controlled laboratory study. After validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology. Inhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control. Pharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model. The NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.
Sections du résumé
BACKGROUND
More than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway.
PURPOSE
To evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair.
STUDY DESIGN
Controlled laboratory study.
METHODS
After validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology.
RESULTS
Inhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control.
CONCLUSION
Pharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model.
CLINICAL RELEVANCE
The NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.
Identifiants
pubmed: 33507808
doi: 10.1177/0363546520985203
pmc: PMC8464217
mid: NIHMS1741698
doi:
Substances chimiques
I-kappa B Kinase
EC 2.7.11.10
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
780-789Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR057836
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR072623
Pays : United States
Organisme : NIAMS NIH HHS
ID : R56 AR057836
Pays : United States
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