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

Nature Medicine volume 18, pages 1095–1101 (2012)Cite this article

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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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Figure 1: Low bone formation during bone remodeling in Igf1r−/− mice.
Figure 2: Suppressed osteoblast maturation in Igf1r−/− mice.
Figure 3: IGF-1 induces the osteoblastic differentiation of MSCs through the IRS-PI3K-Akt-mTOR pathway.
Figure 4: BRCM induces the osteogenic differentiation of MSCs.
Figure 5: Analysis of IGF-1 and IGFBP3 concentrations in blood, bone marrow and bone matrix in relation to bone mass during the aging of rats.
Figure 6: An increase in IGF-1 concentration in the bone matrix attenuates bone loss.

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Acknowledgements

The project described was supported by grant AR 053973 (X.C.) from NIAMS/NIH. J.C. is supported by grant T32DK007751v from the US National Institutes of Health. The authors thank B.J. Canning (Asthma and Allergy Center, Johns Hopkins University) for providing guinea pig marrow cells.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Lingling Xian, Xiangwei Wu, Lijuan Pang, Michael Lou, Tao Qiu, Janet Crane, Frank Frassica, Liming Zhang, Mei Wan & Xu Cao

  2. School of Medicine, Shihezi University, Shihezi, Xinjiang, China

    Lingling Xian, Xiangwei Wu & Lijuan Pang

  3. Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, Maine, USA

    Clifford J Rosen

  4. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Janet Crane

  5. Laboratorio de Biología Celular, Instituto de Nutrición y Tecnología de los Alimentos (INTA), The University of Chile, Santiago, Chile

    Juan Pablo Rodriguez

  6. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Xiaofeng Jia

  7. Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, New York, USA

    Shoshana Yakar

  8. Department of Genetics and Development, Columbia University, New York, New York, USA

    Shouhong Xuan & Argiris Efstratiadis

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  1. Lingling Xian
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Contributions

L.X., X.W., M.L. and L.P. performed the majority of the experiments, analyzed data and prepared the manuscript. T.Q. maintained mice, collected tissue samples and helped with micro-CT analyses. L.P. helped with the in vitro transwell migration assay. J.P.R. finished the human sample detection. X.J. and L.Z. assisted with rat in vivo experiments. J.C., F.F., C.J.R., S.Y., S.X., A.E. and M.W. provided suggestions for the project and critically reviewed the manuscript. X.C. supervised the project and wrote most of the manuscript.

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Correspondence to Xu Cao.

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Xian, L., Wu, X., Pang, L. et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 18, 1095–1101 (2012). https://doi.org/10.1038/nm.2793

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