TY - JOUR
T1 - Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover
AU - Ogata, Naoshi
AU - Chikazu, Daichi
AU - Kubota, Naoto
AU - Terauchi, Yasuo
AU - Tobe, Kazuyuki
AU - Azuma, Yoshiaki
AU - Ohta, Tomohiro
AU - Kadowaki, Takashi
AU - Nakamura, Kozo
AU - Kawaguchi, Hiroshi
PY - 2000/4
Y1 - 2000/4
N2 - 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)2D3. 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)2D3.
AB - 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)2D3. 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)2D3.
UR - http://www.scopus.com/inward/record.url?scp=17144438059&partnerID=8YFLogxK
U2 - 10.1172/JCI9017
DO - 10.1172/JCI9017
M3 - 学術論文
C2 - 10749573
AN - SCOPUS:17144438059
SN - 0021-9738
VL - 105
SP - 935
EP - 943
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -