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Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors
Open accessAbstract
Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.
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“These effects are related mainly to known benefits of exercise, such as strengthening bones, increasing energy expenditure and improving cognition (Bostrom et al., 2012; Colaianni et al., 2015; Colaianni et al., 2017; Lee et al., 2014; Wrann et al., 2013; Zhang et al., 2017).”
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“Interactions of the αV family of integrins with extracellular matrix proteins such as osteopontin and vitronectin lead to adhesion of osteoclasts to the bone surface followed by bone resorption (Duong et al., 2000; Duong and Rodan, 1998; Flores et al., 1992; Horton et al., 1991).”
Arginyl-glycyl-aspartic acid sequences and fibrinogen binding to platelets
Plow, E., Pierschbacher, M. D., Ruoslahti, E. I., Marguerie, G. A., & Ginsberg, M. H. (1987) · Blood · doi:10.1182/blood.v70.1.110.110 · Cited by 169
Bone Health in Endurance Athletes
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“Importantly, results from endurance exercise trials, particularly in the elderly, are even less convincing, with some studies showing preservation of bone mass and others showing no effect or even bone loss (Braam et al., 2003; Duckham et al., 2013; Scofield and Hecht, 2012).”
Osteocyte Remodeling of the Perilacunar and Pericanalicular Matrix
Qing, H., & Bonewald, L. F. (2009) · International Journal of Oral Science · doi:10.4248/ijos.09019 · Cited by 152 · cited 1×
“Emerging evidence suggests that osteocytes can also directly resorb bone during periods of excessive calcium demand (Qing and Bonewald, 2009) or after ovariectomy (Almeida et al.”
Self-citationSclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading
Spatz, J., Ellman, R., Cloutier, A., Louis, L. D., Vliet, M. V., Suva, L. J., Dwyer, D., Stolina, M., Ke, H. Z., & Bouxsein, M. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1807 · Cited by 150 · cited 1×
“Analysis of femur using μCT—We used high-resolution desktop microcomputed tomography imaging (μCT40, Scanco Medical, Brüttisellen, Switzerland) for analysis as previously reported (Spatz et al., 2013).”
Self-citationThi, M. M., Suadicani, S. O., Schaffler, M. B., Weinbaum, S., & Spray, D. C. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321210110 · Cited by 145
Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin
Agthoven, J. F. V., Xiong, J.-P., Alonso, J. L., Rui, X., Adair, B. D., Goodman, S. L., & Arnaout, M. A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2797 · Cited by 137
Molecular basis for the targeted binding of RGD-containing peptide to integrin αVβ3
Yu, Y.-P., Wang, Q., Liu, Y., & Xie, Y. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.10.072 · Cited by 131
Miller, W. H., Alberts, D., Bhatnagar, P. K., Bondinell, W. E., Callahan, J. F., Calvo, R. R., Cousins, R. D., Erhard, K. F., Heerding, D. A., Keenan, R. M., et al. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm990446u · Cited by 119
Biochemical characterization of the binding of echistatin to integrin alphavbeta3 receptor.
Kumar, C. C., Huiming-Nie, C. P. R., Rogers, C. P., Malkowski, M., Maxwell, E., Catino, J. J., & Armstrong, L. (1997) · PubMed · Cited by 106
Kohrt, W. M., Wherry, S. J., Wolfe, P., Sherk, V. D., Wellington, T., Swanson, C. M., Weaver, C. M., & Boxer, R. S. (2018) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3428 · Cited by 105 · cited 1×
“Consistent with the latter effect, brief bouts of endurance training have been shown to increase bone resorption and stimulate sclerostin, an endogenous inhibitor of bone formation (Baron and Kneissel, 2013; Kohrt et al., 2018; Pickering et al., 2017).”
Ovariectomy/Orchidectomy in Rodents
Idris, A. I. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-415-5_34 · Cited by 89 · cited 24×
“Furthermore, deficiency of FNDC5 inhibited OVX-induced perilacunar enlargement. a manifestation of osteocytic osteolysis, indicating that the phenotype is at least mediated partly through an inactivation of osteocyte function(s), as well as through inhibition of osteoclast number and function.”
InfluentialKeppel, T. R., & Weis, D. D. (2014) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-014-1033-6 · Cited by 85
Factors Affecting Bone Loss in Female Endurance Athletes
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Integrin-mediated signaling in the regulation of osteoclast adhesion and activation
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Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential
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“Anti-sclerostin antibodies increase bone mass dramatically in humans but also may have cardiovascular side-effects that could limit their use in practice (McClung, 2017).”
Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains
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“Importantly, they bind to a wide range of different receptors, including fibroblast growth factor receptor and hemojuvelin (Kiselyov et al., 2003; Yang et al., 2008).”
Human Integrin αvβ5: Homology Modeling and Ligand Binding
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“Interestingly, these regions or motifs in integrin β5 have been previously reported to interact with ligands such as fibronectin, osteopontin and vitronectin (Hu et al., 1995; Humphries et al., 2006; Marinelli et al., 2004; Smith et al., 1990; Van Agthoven et al., 2014).”
Lark, M. W., Stroup, G. B., Dodds, R. A., Kapadia, R. D., Hoffman, S. J., Hwang, S. M., James, I. E., Lechowska, B., Liang, X. G., Rieman, D. J., et al. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.2.319 · Cited by 56 · cited 4×
“In addition, we tested irisin-induced signaling with other specific inhibitors for integrin αV, such as cyclo RGDyK and SB273005 (Chen et al., 2004; Dechantsreiter et al., 1999; Lark et al., 2001; Miller et al., 2000; Yu et al., 2014).”
InfluentialSerum Sclerostin Increases After Acute Physical Activity
Pickering, M., Simon, M., Sornay‐Rendu, E., Chikh, K., Carlier, M.-C., Raby, A.-L., Szulc, P., & Confavreux, C. B. (2017) · Calcified Tissue International · doi:10.1007/s00223-017-0272-5 · Cited by 52
Muscular strength and bone mineral density in haemodialysis patients
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Bone Geometry According to Menstrual Function in Female Endurance Athletes
Duckham, R. L., Peirce, N. S., Bailey, C. A., Summers, G. D., Cameron, N., & Brooke-Wavell, K. S. F. (2013) · Calcified Tissue International · doi:10.1007/s00223-013-9700-3 · Cited by 26 · cited 1×
“Importantly, results from endurance exercise trials, particularly in the elderly, are even less convincing, with some studies showing preservation of bone mass and others showing no effect or even bone loss (Braam et al., 2003; Duckham et al., 2013; Scofield and Hecht, 2012).”
Resistance exercise training restores bone mineral density in renal transplant recipients
eatemadololama, A. (2017) · Clinical cases in mineral and bone metabolism · doi:10.11138/ccmbm/2017.14.1.157 · Cited by 26
Guo, L. E., Ding, W., & Zheng, L. (2014) · Journal of Nanoscience and Nanotechnology · doi:10.1166/jnn.2014.8691 · Cited by 8
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Exerkines in health, resilience and disease
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., et al. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00641-2 · Cited by 927
Challenges and advances in clinical applications of mesenchymal stromal cells
Zhou, T., Yuan, Z., Weng, J., Pei, D., Du, X., He, C., & Lai, P. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01037-x · Cited by 712
Robling, A. G., & Bonewald, L. F. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034332 · Cited by 539
Exercise hormone irisin is a critical regulator of cognitive function
Islam, M. R., Valaris, S., Young, M. F., Haley, E. B., Luo, R., Bond, S. F., Mazuera, S., Kitchen, R. R., Caldarone, B. J., Bettio, L. E. B., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00438-z · Cited by 403
Self-citationThe Regulation of Bone Metabolism and Disorders by Wnt Signaling
Maeda, K., Kobayashi, Y., Koide, M., Uehara, S., Okamoto, M., Ishihara, A., Kayama, T., Saito, M., & Marumo, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225525 · Cited by 360
Metadata
- Authors
- Kim, H., Wrann, C. D., Jedrychowski, M., Vidoni, S., Kitase, Y., Nagano, K., Zhou, C., Chou, J., Parkman, V.-J. A., Novick, S. J., Strutzenberg, T. S., Pascal, B. D., Le, P. T., Brooks, D. J., Roche, A. M., Gerber, K. K., Mattheis, L., Chen, W., Tu, H., Bouxsein, M. L., Griffin, P. R., Baron, R., Rosen, C. J., Bonewald, L. F., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Indiana University Indianapolis (US)
- Scripps Research Institute (US)
- Maine Medical Center Research Institute (US)
- Beth Israel Deaconess Medical Center (US)
- LakePharma (United States) (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Kim, Hyeonwoo
- Wrann, Christiane D.
- Vidoni, Sara
- Kitase, Yukiko
- Nagano, Kenichi
- Zhou, Chenhe
- Chou, Joshua
- Novick, Scott J.
- Strutzenberg, Timothy S.
- Pascal, Bruce D.
- Brooks, Daniel J.
- Roche, Alexander M.
- Chen, Wenjing
- Tu, Hua
- Bouxsein, Mary L.
- Griffin, Patrick R.
- Baron, Roland
- Rosen, Clifford J.
- Bonewald, Lynda F.
- Spiegelman, Bruce M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 175
- Issue
- 7
- Pages
- 1756-1768.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6707723
- OpenAlex
- W2905310978
- Cited by
- 638
- References
- 91
- Citations by year
- 2026: 66 · 2025: 96 · 2024: 93 · 2023: 83 · 2022: 100 · 2021: 94 · 2020: 59 · 2019: 44 · 2018: 1
- FWCI
- 17.61
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-07-11)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- NIH (4 R01DK54477-19, DK61502, 5T32HL007374-38, K99NS087096, PO1AG039335, NIDDK RC2 092759)
- JPB Foundation (6293803)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- irisin, FNDC5, ITGAV, osteocytes, osteolysis, sclerostin, bone remodeling, adipose tissue, physical activity, ovariectomy, bone loss, integrin signaling
- MeSH terms
- Adipose Tissue, Animals, Female, Fibronectins, Humans, Osteocytes, Osteolysis, Bone Remodeling, Adipocytes, Integrin alphaV, Cell Line, Tumor, Mice, HEK293 Cells
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