Osteoblastic IRS-1 Essential for Maintaining Bone Turnover in Mice

April 17, 2000

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WESTPORT, Apr 11 (Reuters Health) - Mice that lack the insulin receptor

substrate-1 (IRS-1) gene have low-turnover osteopenia due to osteoblasts that

exhibit impaired proliferation, differentiation and support of

osteoclastogenesis, Japanese researchers report in the April issue of the

Journal of Clinical Investigation.

Dr. Hiroshi Kawaguchi and colleagues of the University of Tokyo in Japan

generated mice that lacked the IRS-1 gene, which exhibited severe osteopenia

with low bone turnover.

Because osteoblasts, but not osteoclasts, from wild-type mice expressed IRS-1,

Dr. Kawaguchi's team treated osteoblasts from IRS-1 deficient mice ex vivo with

insulin or IGF-I. This failed to induce tyrosine phosphorylation of cellular

proteins and the osteoblasts exhibited reduced proliferation and

differentiation.

Further radiologic and histologic analysis of bone phenotypes showed that

osteoclastogenesis depended on IRS-1 expression in the osteoblasts themselves

because the " osteoblasts could not be rescued by IRS-1 expression in hemopoietic

cells in the presence of not only IGF-I but also 1,25 (OH)2D3, " the researchers

report. In addition, IGF-I and 1,25 (OH)2D3 did not induce osteoclast

differentiation factor in osteoblasts from IRS-1 deficient mice.

" Osteoblastic IRS-1 plays a critical role in maintaining bone turnover, not only

because it is essential for IGF-I and insulin signaling, but also because it may

be involved in signal transduction for other factors such as 1,25 (OH)2D3, " Dr.

Kawaguchi and colleagues believe.

The researchers further suggest that IRS-1 deficient mice " could be a new

laboratory animal model for low-turnover osteoporosis and could give us a new

clue to understanding the mechanism of bone turnover regulation. "

J Clin Invest 2000;105:935-943.

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