Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover.
Insulin receptor substrates (IRS-1 and -2) are essential for intracellular signaling by insulin and IGF-I, anabolic regulators of bone metabolism. Mice lacking the IRS-1 gene IRS-1(-/-) showed severe osteopenia with low bone turnover. IRS-1 was expressed in osteoblasts, but not in osteoclasts, of wild-type (WT) mice. IRS-1(-/-) osteoblasts treated with insulin or IGF-I failed to induce tyrosine phosphorylation of cellular proteins, and they showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS-1 expression in osteoblasts and could not be rescued by IRS-1 expression in hemopoietic cells in the presence of not only IGF-I but also 1,25(OH)(2)D(3). In addition, osteoclast differentiation factor (RANKL/ODF) was not induced by these factors in IRS-1(-/-) osteoblasts. We conclude that IRS-1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Osteoblastic IRS-1 is essential for maintaining bone turnover, because it mediates signaling by IGF-I and insulin and, we propose, also by other factors, such as 1,25(OH)(2)D(3).
Ogata
N
N
Department of Orthopaedic Surgery, and. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Chikazu
D
D
Kubota
N
N
Terauchi
Y
Y
Tobe
K
K
Azuma
Y
Y
Ohta
T
T
Kadowaki
T
T
Nakamura
K
K
Kawaguchi
H
H
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000254:growth & development; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013977:Tibia / Q000254:growth & development
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins