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Cited by 631Bone Metabolism and DiseasesBone health and osteoporosis researchGrowth Hormone and Insulin-like Growth Factors

Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells

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Xian, Lingling, Wu, Xiangwei, Pang, Lijuan, Lou, Michael, Rosen, Clifford J, Qiu, Tao, Crane, Janet, Frassica, Frank +8 more·2012·Nature Medicine
DOI 10.1038/nm.2793PMC PMC3438316
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Abstract

Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.

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Authors
Xian, L., Wu, X., Pang, L., Lou, M., Rosen, C. J., Qiu, T., Crane, J., Frassica, F., Zhang, L., Rodriguez, J. P., Jia, X., Yakar, S., Xuan, S., Efstratiadis, A., Wan, M., & Cao, X.
Affiliations
  • Shihezi University (CN)
  • Johns Hopkins University (US)
  • Maine Medical Center Research Institute (US)
  • University of Chile (CL)
  • Icahn School of Medicine at Mount Sinai (US)
  • Columbia University (US)
Corresponding author
Cao, Xu
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2012-06-24
Volume
18
Issue
7
Pages
1095-1101
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2793
PMC
PMC3438316
OpenAlex
W1971887776
Cited by
631
References
3
Citations by year
2026: 30 · 2025: 41 · 2024: 40 · 2023: 44 · 2022: 52 · 2021: 54 · 2020: 58 · 2019: 53 · 2018: 49 · 2017: 43 · 2016: 51 · 2015: 47 · 2014: 29 · 2013: 33 · 2012: 7
FWCI
14.90
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Universidad de Chile (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080898, T32DK007751, T32DK007751V, R01DK057501)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 053973, R01AR053973, R01AR045433, K01AR060433)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
insulin-like growth factor I, IGF-1 receptor, mesenchymal stem cells, mTOR signaling, osteogenic differentiation, bone remodeling, bone mass maintenance, bone resorption, senile osteoporosis, IGF binding protein-3, bone marrow, bone matrix, bone microarchitecture
MeSH terms
Aging, Animals, Bone and Bones, Bone Matrix, Bone Resorption, Cell Count, Cell Differentiation, Enzyme Activation, Femur, Humans, Immunohistochemistry, Insulin-Like Growth Factor I, Organ Size, Osteoblasts, Osteogenesis, Receptor, IGF Type 1, Mice, Knockout, Insulin-Like Growth Factor Binding Protein 3, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Mice, Rats, X-Ray Microtomography, Insulin Receptor Substrate Proteins, TOR Serine-Threonine Kinases, Mesenchymal Stem Cells

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