Insulin Receptor substrate-1 in Osteoblast Is Indispensable for Maintaining Bone Turnover

J Clin Invest. 2000 Apr;105(7):935-43. doi: 10.1172/JCI9017.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Diseases, Metabolic / etiology
  • Bone Diseases, Metabolic / metabolism
  • Bone Diseases, Metabolic / pathology
  • Bone Remodeling*
  • Cells, Cultured
  • Female
  • Femur / growth & development
  • Insulin Receptor Substrate Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / physiology*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteoporosis / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Signal Transduction
  • Tibia / growth & development


  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins