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Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):12157-62. doi: 10.1073/pnas.1516622112. Epub 2015 Sep 15.

The myokine irisin increases cortical bone mass.

Author information

1
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
2
The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
3
Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020 Ancona, Italy;
4
Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy;
5
Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Blindern, N-0317 Oslo, Norway.
6
The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029; mone.zaidi@mssm.edu maria.new@mssm.edu maria.grano@uniba.it.
7
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy; mone.zaidi@mssm.edu maria.new@mssm.edu maria.grano@uniba.it.

Abstract

It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity.

KEYWORDS:

mechanical loading; osteoporosis; sarcopenia

Comment in

PMID:
26374841
PMCID:
PMC4593131
DOI:
10.1073/pnas.1516622112
[Indexed for MEDLINE]
Free PMC Article

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