Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Kim, Hyeonwoo; Wrann, Christiane D.; Jedrychowski, Mark P.; Vidoni, Sara; Kitase, Yukiko; Nagano, Kenichi; Zhou, Chenhe; Chou, Joshua; Parkman, Virginia; Novick, Scott J.; Strutzenberg, Timothy S.; Pascal, Bruce D.; Le, Phuong; Brooks, Daniel J.; Roche, Alexander M.; Gerber, Kaitlyn K.; Mattheis, Laura; Chen, Wenjing; Tu, Hua; Bouxsein, Mary L.; Griffin, Patrick R.; Baron, Ralf; Rosen, Clifford J.; Bonewald, Lynda F.; Spiegelman, Bruce M.

doi:10.1016/j.cell.2019.06.028

Cited by 65 publications

(83 citation statements)

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“…The aim of our study was to determine the effects of rec‐irisin on osteocyte function and survival. Numerous works by us and other groups have shown that irisin targets bone tissue mainly by increasing osteoblast differentiation and activity, but new recent findings have proved that irisin also acts on osteocytes via integrin αV/β5 receptor activating phosphorylation of focal adhesion kinase (FAK) and cyclic AMP response element‐binding protein (CREB) . In the present study, we show that irisin treatment in MLO‐Y4 osteocytes rapidly activates phosphorylation of Erk1/Erk2 after only 5 min and increases Atf4 mRNA expression after 8 hours of treatment.…”

Section: Discussionsupporting

confidence: 42%

“…For instance, the exercise‐induced myokine β‐aminoisobutyric acid (BAIBA) protects osteocytes against ROS‐induced apoptosis and prevents both bone and muscle loss . Noteworthy, it has been recently shown that another myokine, irisin, inhibited hydrogen peroxide–induced apoptosis in the MLO‐Y4 (osteocyte‐like) cell line …”

Section: Introductionmentioning

confidence: 99%

“…As a potential mechanism by which irisin counteracts bone loss, molecular studies have shown that in cortical bone of unloaded mice treated with irisin, sclerostin levels are maintained at the level of normally ambulating control mice, whereas the absence of load increased its expression . Recently, Kim and colleagues identified integrin αV/β5 as the receptor for irisin on osteocytes, paving the way to research on its downstream signaling cascades and the biological effects of irisin on these cells.…”

Section: Introductionmentioning

confidence: 99%

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Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Storlino

Colaianni

Sanesi

et al. 2019

Journal of Bone and Mineral Research

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Previous results showed that intermittently administered irisin improves bone mass in normal mice and prevents the development of disuse‐induced osteoporosis and muscular atrophy in hindlimb‐suspended mice, a murine model able to mimic the absence of mechanical loading. A recent study showed that irisin increases survival of osteocytes acting through integrin αV/β5 receptors. To better understand the action of irisin on these cells, we investigated the downstream signaling cascades in osteocyte‐like cells (MLO‐Y4) treated with recombinant irisin (rec‐irisin) in vitro and we analyzed survival of osteocytes and caspase activation in cortical bone of osteoporotic mice treated with rec‐irisin in vivo. Our results revealed that rec‐irisin activated the MAP kinases Erk1 and Erk2 and increased the expression of the transcription factor Atf4 (2.5‐fold, p < .05) through an Erk‐dependent pathway in osteocytes. Some key genes expressed by MLO‐Y4 cells were modulated by long‐term irisin treatment, either continuously administered or given with intermittent short pulses. Interestingly, Sost mRNA was severely downregulated only upon intermittent irisin administration (10‐fold, p < .001). Furthermore, rec‐irisin upregulated Tfam mRNA (fourfold, p < .05) and Bcl2/Bax ratio (twofold, p < .05) in MLO‐Y4 cells. By detecting caspase‐9 and caspase‐3, we also found that rec‐irisin inhibited apoptosis induced by hydrogen peroxide and dexamethasone, respectively. In cortical bone of unloading C57BL6 mice treated with vehicle (unload‐veh), irisin prevented disuse‐induced reduction of viable osteocytes (+30% versus unload‐veh, p < .05) and increase of empty lacunae (+110% versus unload‐veh, p < .05), as well as caspase‐9 (threefold, p < .05) and caspase‐3 (twofold, p < .05) activations. Our findings revealed underlying mechanisms of irisin action on osteocytes, which increases their functions and exerts anti‐apoptotic effects, confirming that mechanosensor cells of bone are sensitive to the exercise‐mimetic myokine irisin. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 42%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Storlino

Colaianni

Sanesi

et al. 2019

Journal of Bone and Mineral Research

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“…Subsequent studies have shown that irisin is involved in obesity, cardiovascular diseases, telomere length and ageing, and hippocampal neurogenesis . Moreover, a recent study verified that irisin can directly bind to the αv class of integrin receptors in osteocytes . Previous studies have demonstrated that gut barrier dysfunction after gut IR is mainly caused by metabolic disorders and destruction of enterocytes, which can benefit from exercise .…”

Section: Discussionmentioning

confidence: 92%

“…In addition, many studies have shown that irisin can facilitate AMPK activation to further regulate energy metabolism . A recent study indicated that irisin restrains bone loss by binding to the αv class of integrins in osteocytes . However, the effect of exogenous irisin on gut barrier function has not been elucidated to date.…”

Section: Introductionmentioning

confidence: 99%

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor

Zhang

Ren

et al. 2019

J Cellular Molecular Medi

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Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco‐2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK‐UCP 2 pathway via binding to the integrin αVβ5 receptor. Inhibition of integrin αVβ5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVβ5‐AMPK‐UCP 2 pathway.

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Develop Targeted Protein Drug Carriers through a High‐Throughput Screening Platform and Rational Design

Li,

Zuo,

Lin

et al. 2024

Adv Healthcare Materials

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Protein‐based drugs offer advantages such as high specificity, low toxicity, and minimal side effects compared to small molecule drugs. However, delivery of proteins to target tissues or cells remains challenging due to the instability, diverse structures, charges, and molecular weights of proteins. Polymers have emerged as a leading choice for designing effective protein delivery systems, but identifying a suitable polymer for a given protein is complicated by the complexity of both proteins and polymers. To address this challenge, we developed a fluorescence‐based high‐throughput screening platform called ProMatch to efficiently collect data on protein‐polymer interactions, followed by in vivo and in vitro experiments with rational design. Using this approach to streamline polymer selection for targeted protein delivery, we identified candidate polymers from commercially available options and developed a polyhexamethylene biguanide (PHMB)‐based system for delivering proteins to white adipose tissue as a treatment for obesity. We also developed a branched polyethylenimine (bPEI)‐based system for neuron‐specific protein delivery to stimulate optic nerve regeneration. Our high‐throughput screening methodology expedites identification of promising polymer candidates for tissue‐specific protein delivery systems, thereby providing a platform to develop innovative protein‐based therapeutics.This article is protected by copyright. All rights reserved

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Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Cited by 65 publications

References 0 publications

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor

Develop Targeted Protein Drug Carriers through a High‐Throughput Screening Platform and Rational Design

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