Oral Ibuprofen Interferes with Cellular Healing Responses in a Murine Model of Achilles Tendinopathy

Bittermann, Adam; Gao, Shu‐guang; Rezvani, Sabah N.; Li, Jun; Sikes, Katie J; Sandy, John D.; Wang, Vincent; Lee, Simon; Holmes, George B.; Lin, Jui-Wei; Plaas, Anna

doi:10.23937/2572-3243.1510049

Cited by 14 publications

(10 citation statements)

References 52 publications

(69 reference statements)

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“…with IL-1β, has been shown to increase tenocyte migration and proliferation, the capacity for which decreases with age. 80,83,87,88,[100][101][102][103][104][105][106] In this study, we observed a decrease in tenocyte migration and proliferation following inflammatory stimulation in all species (statistically significant for sheep tenocyte proliferation as well as rat and mouse tendon cell migration under constant inflammation) except rats (non-significant trend toward increased proliferation), which may be due to our use of tenocytes from individuals in diseaserelevant age groups. The overall gene expression of human tenocytes was most similar to murine under healthy, equine under transient and ovine under constant inflammatory conditions.…”

Section: Discussionmentioning

confidence: 61%

Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research

Oreff

Fenu

Vogl

et al. 2021

Preprint

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For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.

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Section: Discussionmentioning

confidence: 61%

Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research

Oreff

Fenu

Vogl

et al. 2021

Preprint

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“…In a murine model of Achilles tendinopathy, administration of ibuprofen during the inflammatory stage of healing interfered with extracellular matrix remodeling and ultimately led to decreased tensile strength in the healed tendon. 105 Similar results, including abnormal fiber organization and decreased tensile strength, were seen in a rat model of tendinopathy where ibuprofen was delivered in the first week after injury. However, when delivered after 1 week following injury, no detrimental effects were seen, suggesting that NSAIDs interfere in tendon healing in a time dependent manner, most pronounced in the early, inflammatory phase of healing.…”

Section: Nsaid Usementioning

confidence: 53%

Post‐Procedure Protocols Following Platelet‐Rich Plasma Injections for Tendinopathy: A Systematic Review

Townsend

Rickenbach

Bailowitz

et al. 2020

PM&R

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Objective Platelet‐rich plasma (PRP) has been increasingly studied as a treatment for tendinopathy. Many factors may influence outcomes after PRP, including different protocols following administration. It was hypothesized that there would be heterogeneity in post‐PRP protocols. Literature Survey A systematized review of the literature on post‐PRP protocols for tendinopathy was conducted using an electronic search of MEDLINE and Embase databases through September 2018. Methodology After duplicates were removed, English language articles involving adult patients who received PRP for tendinopathy were reviewed. Exclusion criteria included studies with fewer than 10 patients, PRP used to treat pathology other than tendinopathy, multiple protocols in one study, and surgical settings. Protocol specifics were extracted including nonsteroidal anti‐inflammatory drugs (NSAID) restrictions before and after injection, postinjection restrictions on movement and weight bearing, use of orthoses, activity modifications, and postinjection rehabilitation protocols. Given limitations in the data, a meta‐analysis was not performed. Synthesis Eighty‐four studies met inclusion criteria. Following PRP injection, weight‐bearing restrictions were mentioned rarely (12% of protocols). Orthosis use was uncommon overall (18%) but more common in Achilles tendinopathy protocols (53%). The majority of protocols instituted a period of stretching (51%) and strengthening (54%). Stretching programs generally began 2‐7 days following injection, and strengthening programs began within 2‐3 weeks. Preinjection NSAID restriction was reported rarely (20%), whereas postinjection NSAID restriction was more common (56%), with a typical restriction of greater than 2 weeks (38%). Return to play or full activity was reported in 42% of protocols, most commonly at 4‐6 weeks following injection. Conclusion Although the clinical effectiveness of PRP remains controversial, even less is known about the effect of post‐PRP protocols, which may affect the outcomes attributed to PRP itself. No studies directly compare post‐PRP protocols, and the protocols studied demonstrate substantial heterogeneity. Some consensus regarding post‐PRP protocols exists, although the rationale for these recommendations is limited.

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“…For example, NSAIDs treatment suppressed extracellular matrix remodeling and cellular responses in a tendinopathy animal model. 3,9 NSAIDs led to decreased 7,9 or no effect 13,42 on tendon mechanical properties after repair. Rather than completely suppressing the inflammatory response, small-molecule inhibitors can be used to selectively block a specific part of a pathway (eg, the inflammatory arm of NF-κB) to maintain the positive inflammatory response necessary for initiating tendon healing while suppressing the detrimental effects of sustained inflammation.…”

Section: Discussionmentioning

confidence: 93%

“…16 However, broadly suppressing inflammation through nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used postoperatively, is also detrimental to healing. 3,9,13 Therefore, a carefully balanced inflammatory response is necessary for optimal healing (eg, by modulating inflammation at the earliest stages after repair 20 ).…”

mentioning

confidence: 99%

Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model

Golman

Skouteris

et al. 2021

Am J Sports Med

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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.

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Oral Ibuprofen Interferes with Cellular Healing Responses in a Murine Model of Achilles Tendinopathy

Cited by 14 publications

References 52 publications

Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research

Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research

Post‐Procedure Protocols Following Platelet‐Rich Plasma Injections for Tendinopathy: A Systematic Review

Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model

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