The effects of NF-κB suppression on the early healing response following intrasynovial tendon repair in a canine model.

Autor: Lane RA; Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri, USA., Migotsky N; Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri, USA.; Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA., Havlioglu N; Department of Pathology, John Cochran VA Medical Center, St. Louis, Missouri, USA., Iannucci LE; Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA., Shen H; Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri, USA., Lake S; Mechanical Engineering & Materials Science, Washington University, St. Louis, Missouri, USA., Sakiyama-Elbert SE; Department of Biomedical Engineering, University of Washington, Seattle, Washington, USA., Thomopoulos S; Department of Orthopaedic Surgery, Columbia University, New York City, New York, USA.; Department of Biomedical Engineering, Columbia University, New York City, New York, USA., Gelberman RH; Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri, USA.
Jazyk: angličtina
Zdroj: Journal of orthopaedic research : official publication of the Orthopaedic Research Society [J Orthop Res] 2023 Oct; Vol. 41 (10), pp. 2295-2304. Date of Electronic Publication: 2023 May 04.
DOI: 10.1002/jor.25576
Abstrakt: The highly variable clinical outcomes noted after intrasynovial tendon repair have been associated with an early inflammatory response leading to the development of fibrovascular adhesions. Prior efforts to broadly suppress this inflammatory response have been largely unsuccessful. Recent studies have shown that selective inhibition of IkappaB kinase beta (IKK-β), an upstream activator of nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling, mitigates the early inflammatory response and leads to improved tendon healing outcomes. In the current study, we test the hypothesis that oral treatment with the IKK-β inhibitor ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinenitrile an inhibitor) will modulate the postoperative inflammatory response and improve intrasynovial flexor tendon healing. To test this hypothesis, the flexor digitorum profundus tendon of 21 canines was transected and repaired within the intrasynovial region and assessed after 3 and 14 days. Histomorphometry, gene expression analyses, immunohistochemistry, and quantitative polarized light imaging were used to examine ACHP-mediated changes. ACHP led to reduction in phosphorylated p-65, indicating that NF-κB activity was suppressed. ACHP enhanced expression of inflammation-related genes at 3 days and suppressed expression of these genes at 14 days. Histomorphometry revealed enhanced cellular proliferation and neovascularization in ACHP-treated tendons compared with time-matched controls. These findings demonstrate that ACHP effectively suppressed NF-κB signaling and modulated early inflammation, leading to increased cellular proliferation and neovascularization without stimulating the formation of fibrovascular adhesions. Together, these data suggest that ACHP treatment accelerated the inflammatory and proliferative phases of tendon healing following intrasynovial flexor tendon repair. Clinical Significance: Using a clinically relevant large-animal model, this study revealed that targeted inhibition of nuclear factor kappa-light chain enhancer of activated B cells signaling with ACHP provides a new therapeutic strategy for enhancing the repair of sutured intrasynovial tendons.
(© 2023 Orthopaedic Research Society.)
Databáze: MEDLINE
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