The multiscale structural and mechanical effects of mouse supraspinatus muscle unloading on the mature enthesis

Deymier, Alix C.; Schwartz, Andrea G.; Cai, Zhengguo; Daulton, T. L.; Pasteris, Jill Dill; Genin, Guy M.; Thomopoulos, Stavros

doi:10.1016/j.actbio.2018.10.024

Cited by 57 publications

(81 citation statements)

References 71 publications

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“…Reduced loading could result in significant structural consequences at several hierarchical scales, with an increased risk of mechanical failure, as demonstrated in mouse models. 64 Finally, in keeping with this finding, some reports showed that many patients with axSpA reported injuries or trauma as a potential trigger for their disease onset. 62 65 …”

Section: The Role Of Physical Exercise In Axspa: To Move or Not To Momentioning

confidence: 53%

To move or not to move: the paradoxical effect of physical exercise in axial spondyloarthritis

Perrotta

Lories²,

Lubrano

2021

RMD Open

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In the last years, new researches focused on the role of biomechanical stress and microdamage in the pathogenesis of inflammatory arthritis and, in particular, in axial spondyloarthritis (axSpA). Animal models showed how entheseal stress and physical exercise could contribute to the development of inflammation and new bone formation at entheseal and articular sites, by activating innate immune system and the release of cytokines. Furthermore, clues of the involvement of biomechanical stress in the development of axSpA are present in clinical experiences. However, rehabilitation and exercise programmes are the cornerstone of treatment for axSpA, reducing disease activity and improving spinal function and quality of life. The concept of mechanical stress as a contributor to disease development and progression represents, potentially, a conceptual challenge for this approach. The aim of this review is to discuss the current evidence on the intriguing contribution of the biomechanical stress to the pathogenesis of inflammation and new bone formation and to evaluate and reflect on the role of exercise in the treatment and in the management of the disease, considering both the beneficial effects and its possible paradoxical action.

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Section: The Role Of Physical Exercise In Axspa: To Move or Not To Momentioning

confidence: 53%

To move or not to move: the paradoxical effect of physical exercise in axial spondyloarthritis

Perrotta

Lories²,

Lubrano

2021

RMD Open

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“…This pattern, which involved smaller muscle volume in the stimulated limbs, is a normal adaptation to reduce muscle fatigue by increasing the relative abundance of narrower fiber types 27 (also see below). The results of a recent experimental study on adult mice established a direct association between unloading and bone loss at entheseal areas 26 . On this basis, the observed entheseal differences between stimulated and unstimulated limbs may be due to a combination of increased and decreased muscle use, respectively.…”

Section: Discussionmentioning

confidence: 95%

“…18 ). Moreover, recent experimental research on adult mice entheses 26 found that artificial muscle paralysis for 21 days led to significant bone loss in entheseal areas at the millimeter scale.…”

Section: Introductionmentioning

confidence: 99%

Experimental proof that multivariate patterns among muscle attachments (entheses) can reflect repetitive muscle use

Karakostis

Jeffery

Harvati

2019

Sci Rep

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Reconstructions of habitual activity in past populations and extinct human groups is a primary goal of paleoanthropological research. Muscle attachment scars (entheses) are widely considered as indicators of habitual activity and many attempts have been made to use them for this purpose. However, their interpretation remains equivocal due to methodological limitations and a paucity of empirical data supporting an interaction between systematic muscle forces and entheseal morphology. We have recently addressed the first issue with precise three-dimensional measuring protocols and rigorous multivariate analysis focusing on the patterns among different entheses rather than comparing each entheseal structure separately. In a previous study, the resulting entheseal correlations reflected synergistic muscle groups that separated individuals according to their lifelong occupational activities. Here we address the second issue by applying this methodology to existing micro-computed tomography data from rats that have undergone muscle stimulation under experimental conditions. In contrast to previous animal studies, we relied on blind analytical procedures across two research institutions and controlled for most factors of interindividual variability. Results demonstrated that the multivariate associations among different entheseal surfaces can directly reflect repetitive muscle recruitment and provide essential information on muscle use.

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“…The IKKβ inhibitor was administered orally, leading to a systemic effect, including to the humeral head bone adjacent to the healing interface. Because mineral content correlates with tendon enthesis mechanical properties 12 and loss of mineralized tissue at the attachment site correlates with higher rates of retearing after surgical repair, 15 we examined bone morphometry of the humeral head. While IKKβ inhibitor treatment prevented some of the mineral and trabeculae losses that are commonly seen after rotator cuff repair, systemic inhibition of IKKβ also led to decreases in overall humeral head BV/TV and cortical thickness at an earlier timepoint.…”

Section: Discussionmentioning

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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The multiscale structural and mechanical effects of mouse supraspinatus muscle unloading on the mature enthesis

Cited by 57 publications

References 71 publications

To move or not to move: the paradoxical effect of physical exercise in axial spondyloarthritis

To move or not to move: the paradoxical effect of physical exercise in axial spondyloarthritis

Experimental proof that multivariate patterns among muscle attachments (entheses) can reflect repetitive muscle use

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

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