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Regulation of IGF‐1 signaling by integrins in bone: Role of mechanical loading
Author(s) -
Long Roger K,
Sakata T,
Elalieh H Z,
Halloran B P,
Bikle D D
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a417
Subject(s) - integrin , microbiology and biotechnology , signal transduction , chemistry , biology , receptor , biochemistry
Skeletal unloading by hindlimb suspension results in diminished bone formation associated with altered proliferation and differentiation of osteoprogenitor cells and decreased number and function of osteoblasts. This is associated with resistance to IGF‐1. Therefore, alterations of the IGF‐1 signaling pathway were evaluated to characterize the osteopenic changes of skeletal unloading. Twelve week old GH deficient (dw‐4) and Sprague‐Dawley rats were hindlimb unloaded by tail suspension for 7 and 14 days. In vivo IGF‐1 administration (2.5mg/kg/day) to unloaded animals revealed unloading‐induced IGF‐1 resistance. Bone formation rates at the tibiofibular junction were significantly reduced by 30–40% and the stimulatory effects of IGF‐1 blunted by unloading. Assessment of bone marrow osteoprogenitor (BMOp) cells from unloaded animals demonstrated significantly decreased numbers that failed to increase with in vivo IGF‐1 treatment. BMOp cells from unloaded animals failed to respond to in vitro IGF‐1 stimulation with respect to activation of the IGF‐1 receptor and subsequent activation of the ras/MAPK/ERK and PI3K/Akt pathways. Alterations of the IGF‐1 signaling pathway were not secondary to increased phosphatase activity or altered ligand‐receptor binding. Inhibition of integrin signaling by the disintegrin, echistatin, recapitulated the unloading phenotype by blunting IGF‐1 stimulated IGF‐1 receptor phosphorylation and cell proliferation. Additionally, mRNA expression of multiple integrin subunits was reduced by 50–90% in BMOp cells from unloaded animals compared to loaded controls. We conclude that integrin signaling plays a critical role in IGF‐1 signaling and contributes to the resistance to IGF‐1 induced by skeletal unloading. Supported by NIH RO1 DK54793 and NASA NAG 2‐1371.