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  • Review Article
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Targeting integrins to promote bone formation and repair

Nature Reviews Endocrinology volume 9, pages 288–295 (2013)Cite this article

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Abstract

The ageing skeleton experiences a progressive decline in the rate of bone formation, which can eventually result in osteoporosis—a common disease characterized by reduced bone mass and altered bone microarchitecture which can result in fractures. One emerging therapy involves the identification of molecules that target bone-marrow mesenchymal stromal cells (MSCs) and promote their differentiation into osteoblasts, thereby counteracting bone loss. This Review highlights the discovery that some integrins, a family of heterodimeric transmembrane proteins that can interact with matrix proteins and generate intracellular signals, can be targeted to promote homing of MSCs to bone, osteogenic differentiation and bone formation. Specifically, priming of the α5β1 integrin, which is required for osteoblastic differentiation of MSCs, leads to increased bone formation and improved bone repair in mice. Additionally, treatment with a peptidomimetic ligand of the α4β1 integrin coupled to an agent with a high affinity for bone improves the homing of MSCs to bone and promotes osteoblast differentiation and bone formation, leading to increased bone mass in osteopenic mice. Strategies that target key integrins expressed by MSCs might, therefore, translate into improved therapies for age-related bone loss and possibly other disorders.

Key Points

  • Novel approaches for promoting osteogenic differentiation of mesenchymal stromal cells (MSCs) and improving bone formation and repair need to be developed for the treatment of age-related skeletal disorders

  • Extracellular matrix–integrin interactions control both osteoblastogenesis and bone formation

  • Complexes of integrin-targeted agents associated with an antiosteoporotic agent with high affinity for bone showed improved treatment efficacy in osteopenic mouse models

  • Approaches that target α4β1 and α5β1 integrins may lead to the development of novel strategies to increase bone formation in age-related bone loss and promote repair of non-healing fractures in humans

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Figure 1: Osteoblastogenesis is controlled by integrins.
Figure 2: Integrin-mediated signals that regulate osteoblastogenesis.
Figure 3: Novel integrin-targeted approaches that promote homing of MSCs to bone, osteoblast differentiation, bone formation and repair.

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References

  1. Raisz, L. G. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest. 115, 3318–3325 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Khosla, S. & Riggs, B. L. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol. Metab. Clin. North Am. 34, 1015–1030 (2005).

    CAS  PubMed  Google Scholar 

  3. Riggs, B. L. & Parfitt, A. M. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J. Bone Miner. Res. 20, 177–184 (2005).

    CAS  PubMed  Google Scholar 

  4. Marie, P. J. & Kassem, M. Osteoblasts in osteoporosis: past, emerging and future anabolic targets. Eur. J. Endocrinol. 165, 1–10 (2011).

    CAS  PubMed  Google Scholar 

  5. Kassem, M. & Marie, P. J. Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell 10, 191–197 (2011).

    CAS  PubMed  Google Scholar 

  6. Marie, P. J. & Kassem, M. Extrinsic mechanisms involved in age-related defective bone formation. J. Clin. Endocrinol. Metab. 96, 600–609 (2011).

    CAS  PubMed  Google Scholar 

  7. Aubin, J. E. Regulation of osteoblast formation and function. Rev. Endocr. Metab. Disord. 2, 81–94 (2001).

    CAS  PubMed  Google Scholar 

  8. Lian, J. B. et al. Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors. Crit. Rev. Eukaryot. Gene Expr. 14, 1–41 (2004).

    CAS  PubMed  Google Scholar 

  9. Karsenty, G. Minireview: transcriptional control of osteoblast differentiation. Endocrinology 142, 2731–2733 (2001).

    CAS  PubMed  Google Scholar 

  10. Marie, P. J. Transcription factors controlling osteoblastogenesis. Arch. Biochem. Biophys. 473, 98–105 (2008).

    CAS  PubMed  Google Scholar 

  11. Long, F. Building strong bones: molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol. 13, 27–38 (2012).

    CAS  Google Scholar 

  12. Bianco, P. & Gehron Robey, P. Marrow stromal stem cells. J. Clin. Invest. 105, 1663–1668 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Prockop, D. J., Gregory, C. A. & Spees, J. L. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc. Natl Acad. Sci. USA 100 (Suppl. 1), 11917–11923 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bianco, P. & Robey, P. G. Stem cells in tissue engineering. Nature 414, 118–121 (2001).

    CAS  PubMed  Google Scholar 

  15. Prockop, D. J. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol. Ther. 17, 939–946 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P. G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

    CAS  PubMed  Google Scholar 

  17. Marie, P. J. & Fromigué, O. Osteogenic differentiation of human marrow-derived mesenchymal stem cells. Regen. Med. 1, 539–548 (2006).

    CAS  PubMed  Google Scholar 

  18. Rosen, V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 20, 475–480 (2009).

    CAS  PubMed  Google Scholar 

  19. Bodine, P. V. & Komm, B. S. Wnt signaling and osteoblastogenesis. Rev. Endocr. Metab. Disord. 7, 33–39 (2006).

    CAS  PubMed  Google Scholar 

  20. Plow, E. F., Haas, T. A., Zhang, L., Loftus, J. & Smith, J. W. Ligand binding to integrins. J. Biol. Chem. 275, 21785–21788 (2000).

    CAS  PubMed  Google Scholar 

  21. Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3, 3 (2011).

    Google Scholar 

  22. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  PubMed  Google Scholar 

  23. Mould, A. P. & Humphries, M. J. Regulation of integrin function through conformational complexity: not simply a knee-jerk reaction? Curr. Opin. Cell. Biol. 16, 544–551 (2004).

    CAS  PubMed  Google Scholar 

  24. Luo, B. H. & Springer, T. A. Integrin structures and conformational signaling. Curr. Opin. Cell Biol. 18, 579–586 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Askari, J. A., Buckley, P. A., Mould, A. P. & Humphries, M. J. Linking integrin conformation to function. J. Cell Sci. 122, 165–170 (2009).

    CAS  PubMed  Google Scholar 

  26. Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    CAS  PubMed  Google Scholar 

  27. Mitra, S. K. & Schlaepfer, D. D. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr. Opin. Cell Biol. 18, 516–523 (2006).

    CAS  PubMed  Google Scholar 

  28. Chen, X. & Gumbiner, B. M. Crosstalk between different adhesion molecules. Curr. Opin. Cell Biol. 18, 572–578 (2006).

    CAS  PubMed  Google Scholar 

  29. Damsky, C. H. & Ilic, D. Integrin signaling: it's where the action is. Curr. Opin. Cell Biol. 14, 594–602 (2002).

    CAS  PubMed  Google Scholar 

  30. Ginsberg, M. H., Partridge, A. & Shattil, S. J. Integrin regulation. Curr. Opin. Cell Biol. 17, 509–516 (2005).

    CAS  PubMed  Google Scholar 

  31. Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).

    CAS  PubMed  Google Scholar 

  32. Larsen, M., Artym, V. V., Green, J. A. & Yamada, K. M. The matrix reorganized: extracellular matrix remodeling and integrin signaling. Curr. Opin. Cell Biol. 18, 463–471 (2006).

    CAS  PubMed  Google Scholar 

  33. Bershadsky, A., Kozlov, M. & Geiger, B. Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize. Curr. Opin. Cell. Biol. 18, 472–481 (2006).

    CAS  PubMed  Google Scholar 

  34. Bouvard, D. et al. Functional consequences of integrin gene mutations in mice. Circ. Res. 89, 211–223 (2001).

    CAS  PubMed  Google Scholar 

  35. Bokel, C. & Brown, N. H. Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev. Cell 3, 311–321 (2002).

    CAS  PubMed  Google Scholar 

  36. Sanjay, A., Horne, W. C. & Baron, R. The Cbl family: ubiquitin ligases regulating signaling by tyrosine kinases. Sci. STKE 2001, PE40 (2001).

    CAS  PubMed  Google Scholar 

  37. Duong, L. T., Lakkakorpi, P., Nakamura, I. & Rodan, G. A. Integrins and signaling in osteoclast function. Matrix Biol. 19, 97–105 (2000).

    CAS  PubMed  Google Scholar 

  38. Ross, F. P. & Teitelbaum, S. L. αvβ3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol. Rev. 208, 88–105 (2005).

    CAS  PubMed  Google Scholar 

  39. Del Fattore, A., Teti, A. & Rucci, N. Osteoclast receptors and signaling. Arch. Biochem. Biophys. 473, 147–160 (2008).

    CAS  PubMed  Google Scholar 

  40. Zou, W. & Teitelbaum, S. L. Integrins, growth factors, and the osteoclast cytoskeleton. Ann. NY Acad. Sci. 1192, 27–31 (2010).

    CAS  PubMed  Google Scholar 

  41. Engleman, V. W. et al. A peptidomimetic antagonist of the α(v) β3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J. Clin. Invest. 99, 2284–2292 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lark, M. W. et al. Design and characterization of orally active Arg-Gly-Asp peptidomimetic vitronectin receptor antagonist SB 265123 for prevention of bone loss in osteoporosis. J. Pharmacol. Exp. Ther. 291, 612–617 (1999).

    CAS  PubMed  Google Scholar 

  43. Horton, M. A. Integrin antagonists as inhibitors of bone resorption: implications for treatment. Proc. Nutr. Soc. 60, 275–281 (2001).

    CAS  PubMed  Google Scholar 

  44. Cacciari, B. & Spalluto, G. Non peptidic αvβ3 antagonists: recent developments. Curr. Med. Chem. 12, 51–70 (2005).

    CAS  PubMed  Google Scholar 

  45. Nakamura, I., Duong le, T., Rodan, S. B. & Rodan, G. A. Involvement of α(v)β3 integrins in osteoclast function. J. Bone Miner. Metab. 25, 337–344 (2007).

    CAS  PubMed  Google Scholar 

  46. Crippes, B. A. et al. Antibody to β3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. Endocrinology 137, 918–924 (1996).

    CAS  PubMed  Google Scholar 

  47. Murphy, M. G. et al. Effect of L-000845704, an αvβ3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J. Clin. Endocrinol. Metab. 90, 2022–2028 (2005).

    CAS  PubMed  Google Scholar 

  48. Zhao, H. et al. Critical role of β3 integrin in experimental postmenopausal osteoporosis. J. Bone Miner. Res. 20, 2116–2123 (2005).

    CAS  PubMed  Google Scholar 

  49. Lane, N. E. et al. Mice lacking the integrin β5 subunit have accelerated osteoclast maturation and increased activity in the estrogen-deficient state. J. Bone Miner. Res. 20, 58–66 (2005).

    CAS  PubMed  Google Scholar 

  50. Crotti, T. N. et al. NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation. Gene 372, 92–102 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Rao, H. et al. α9β1: a novel osteoclast integrin that regulates osteoclast formation and function. J. Bone Miner. Res. 21, 1657–1665 (2006).

    CAS  PubMed  Google Scholar 

  52. Damsky, C. H. Extracellular matrix-integrin interactions in osteoblast function and tissue remodeling. Bone 25, 95–96 (1999).

    CAS  PubMed  Google Scholar 

  53. Gronthos, S., Simmons, P. J., Graves, S. E. & Robey, P. G. Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone 28, 174–181 (2001).

    CAS  PubMed  Google Scholar 

  54. Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).

    CAS  PubMed  Google Scholar 

  55. Thompson, W. R., Rubin, C. T. & Rubin, J. Mechanical regulation of signaling pathways in bone. Gene 503, 179–193 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Franceschi, R. T. et al. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect. Tissue Res. 44 (Suppl. 1), 109–116 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Marie, P. J. Bone cell-matrix protein interactions. Osteoporos. Int. 20, 1037–1042 (2009).

    CAS  PubMed  Google Scholar 

  58. Bennett, J. H., Carter, D. H., Alavi, A. L., Beresford, J. N. & Walsh, S. Patterns of integrin expression in a human mandibular explant model of osteoblast differentiation. Arch. Oral Biol. 46, 229–238 (2001).

    CAS  PubMed  Google Scholar 

  59. Shekaran, A. & Garcia, A. J. Extracellular matrix-mimetic adhesive biomaterials for bone repair. J. Biomed. Mater. Res. A 96, 261–272 (2011).

    PubMed  Google Scholar 

  60. Matter, M. L. & Ruoslahti, E. A signaling pathway from the α5β1 and α(v) β3 integrins that elevates bcl-2 transcription. J. Biol. Chem. 276, 27757–27763 (2001).

    CAS  PubMed  Google Scholar 

  61. Howe, A. K., Aplin, A. E. & Juliano, R. L. Anchorage-dependent ERK signaling—mechanisms and consequences. Curr. Opin. Genet. Dev. 12, 30–35 (2002).

    CAS  PubMed  Google Scholar 

  62. Wang, Z., Telci, D. & Griffin, M. Importance of syndecan-4 and syndecan-2 in osteoblast cell adhesion and survival mediated by a tissue transglutaminase-fibronectin complex. Exp. Cell Res. 317, 367–381 (2011).

    CAS  PubMed  Google Scholar 

  63. Kaabeche, K. et al. Cbl-mediated ubiquitination of α5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation. J. Cell Sci. 118, 1223–1232 (2005).

    CAS  PubMed  Google Scholar 

  64. Dufour, C., Holy, X. & Marie, P. J. Skeletal unloading induces osteoblast apoptosis and targets α5β1-PI3K-Bcl-2 signaling in rat bone. Exp. Cell. Res. 313, 394–403 (2007).

    CAS  PubMed  Google Scholar 

  65. Watabe, H., Furuhama, T., Tani-Ishii, N. & Mikuni-Takagaki, Y. Mechanotransduction activates α(5) β(1) integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp. Cell. Res. 317, 2642–2649 (2011).

    CAS  PubMed  Google Scholar 

  66. Batra, N. et al. Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels. Proc. Natl Acad. Sci. USA 109, 3359–3364 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zimmerman, D., Jin, F., Leboy, P., Hardy, S. & Damsky, C. Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts. Dev. Biol. 220, 2–15 (2000).

    CAS  PubMed  Google Scholar 

  68. Globus, R. K. et al. Skeletal phenotype of growing transgenic mice that express a function-perturbing form of β1 integrin in osteoblasts. Calcif. Tissue Int. 76, 39–49 (2005).

    CAS  PubMed  Google Scholar 

  69. Iwaniec, U. T. et al. Effects of disrupted β1-integrin function on the skeletal response to short-term hindlimb unloading in mice. J. Appl. Physiol. 98, 690–696 (2005).

    CAS  PubMed  Google Scholar 

  70. Bouvard, D. et al. Defective osteoblast function in ICAP-1-deficient mice. Development 134, 2615–2625 (2007).

    CAS  PubMed  Google Scholar 

  71. Brunner, M. et al. Osteoblast mineralization requires β1 integrin/ICAP-1-dependent fibronectin deposition. J. Cell Biol. 194, 307–322 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Yeh, C. R. et al. Estrogen augments shear stress-induced signaling and gene expression in osteoblast-like cells via estrogen receptor-mediated expression of β1-integrin. J. Bone Miner. Res. 25, 627–639 (2010).

    CAS  PubMed  Google Scholar 

  73. Park, S. J. et al. The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrin β1 expression. Bone 49, 428–438 (2011).

    CAS  PubMed  Google Scholar 

  74. Nesti, L. J. et al. TGF-β1 calcium signaling increases α5 integrin expression in osteoblasts. J. Orthop. Res. 20, 1042–1049 (2002).

    CAS  PubMed  Google Scholar 

  75. Dufour, C., Holy, X. & Marie, P. J. Transforming growth factor-β prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling. Am. J. Physiol. Endocrinol. Metab. 294, E794–E801 (2008).

    CAS  PubMed  Google Scholar 

  76. Ono, M., Inkson, C. A., Kilts, T. M. & Young, M. F. WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. J. Bone Miner. Res. 26, 193–208 (2011).

    CAS  PubMed  Google Scholar 

  77. Salasznyk, R. M., Klees, R. F., Boskey, A. & Plopper, G. E. Activation of FAK is necessary for the osteogenic differentiation of human mesenchymal stem cells on laminin-5. J. Cell. Biochem. 100, 499–514 (2007).

    CAS  PubMed  Google Scholar 

  78. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell. 6, 483–495 (2004).

    CAS  PubMed  Google Scholar 

  79. Khatiwala, C. B., Kim, P. D., Peyton, S. R. & Putnam, A. J. ECM compliance regulates osteogenesis by influencing MAPK signaling downstream of RhoA and ROCK. J. Bone Miner. Res. 24, 886–898 (2009).

    CAS  PubMed  Google Scholar 

  80. Carvalho, R. S., Bumann, A., Schaffer, J. L. & Gerstenfeld, L. C. Predominant integrin ligands expressed by osteoblasts show preferential regulation in response to both cell adhesion and mechanical perturbation. J. Cell. Biochem. 84, 497–508 (2002).

    CAS  PubMed  Google Scholar 

  81. Pommerenke, H. et al. The mode of mechanical integrin stressing controls intracellular signaling in osteoblasts. J. Bone Miner. Res. 17, 603–611 (2002).

    CAS  PubMed  Google Scholar 

  82. Boutahar, N., Guignandon, A., Vico, L. & Lafage-Proust, M. H. Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 tyrosine sites involved in ERK activation. J. Biol. Chem. 279, 30588–30599 (2004).

    CAS  PubMed  Google Scholar 

  83. Young, S. R., Gerard- O'Riley, R., Kim, J. B. & Pavalko, F. M. Focal adhesion kinase is important for fluid shear stress-induced mechanotransduction in osteoblasts. J. Bone Miner. Res. 24, 411–424 (2009).

    CAS  PubMed  Google Scholar 

  84. Hamidouche, Z. et al. Priming integrin α5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis. Proc. Natl Acad. Sci. USA 106, 18587–18591 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kim, J. B. et al. Reconciling the roles of FAK in osteoblast differentiation, osteoclast remodeling, and bone regeneration. Bone 41, 39–51 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Popov, C. et al. Integrins α2β1 and α11β1 regulate the survival of mesenchymal stem cells on collagen I. Cell. Death Dis. 2, e186 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Shih, Y. R., Tseng, K. F., Lai, H. Y., Lin, C. H. & Lee, O. K. Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. J. Bone Miner. Res. 26, 730–738 (2011).

    CAS  PubMed  Google Scholar 

  88. Cheng, S. L. et al. Regulation of αVβ3 and αVβ5 integrins by dexamethasone in normal human osteoblastic cells. J. Cell. Biochem. 77, 265–276 (2000).

    CAS  PubMed  Google Scholar 

  89. Su, J. L. et al. CYR61 regulates BMP-2-dependent osteoblast differentiation through the αvβ3 integrin/integrin-linked kinase/ERK pathway. J. Biol. Chem. 285, 31325–31336 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Blumbach, K. et al. Dwarfism in mice lacking collagen-binding integrins α2β1 and α11β1 is caused by severely diminished IGF-1 levels. J. Biol. Chem. 287, 6431–6440 (2012).

    CAS  PubMed  Google Scholar 

  91. Tucker, G. C. Integrins: molecular targets in cancer therapy. Curr. Oncol. Rep. 8, 96–103 (2006).

    CAS  PubMed  Google Scholar 

  92. Millard, M., Odde, S. & Neamati, N. Integrin targeted therapeutics. Theranostics 1, 154–188 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cox, D., Brennan, M. & Moran, N. Integrins as therapeutic targets: lessons and opportunities. Nat. Rev. Drug Discov. 9, 804–820 (2010).

    CAS  PubMed  Google Scholar 

  94. Humphries, M. J. Integrin structure. Biochem. Soc. Trans. 28, 311–339 (2000).

    CAS  PubMed  Google Scholar 

  95. Hamidouche, Z., Fromigué, O., Ringe, J., Haüpl, T. & Marie, P. J. Crosstalks between integrin α5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation. BMC Cell Biol. 11, 44 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Fromigué, O. et al. Peptide-based activation of α5 integrin for promoting osteogenesis. J. Cell. Biochem. 113, 3029–3038 (2012).

    PubMed  Google Scholar 

  97. Srouji, S. et al. Lentiviral-mediated integrin α5 expression in human adult mesenchymal stromal cells promotes bone repair in mouse cranial and long-bone defects. Hum. Gene Ther. 23, 167–172 (2012).

    CAS  PubMed  Google Scholar 

  98. Hartz, B. et al. α4 integrin levels on mobilized peripheral blood stem cells predict rapidity of engraftment in patients receiving autologous stem cell transplantation. Blood 118, 2362–2365 (2011).

    CAS  PubMed  Google Scholar 

  99. Kumar, S. & Ponnazhagan, S. Bone homing of mesenchymal stem cells by ectopic α4 integrin expression. FASEB J. 21, 3917–3927 (2007).

    CAS  PubMed  Google Scholar 

  100. Guan, M. et al. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat. Med. 18, 456–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging a4β1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Seeman, E. Pathogenesis of bone fragility in women and men. Lancet 359, 1841–1850 (2002).

    PubMed  Google Scholar 

  103. Anselme, K. Osteoblast adhesion on biomaterials. Biomaterials 21, 667–681 (2000).

    CAS  PubMed  Google Scholar 

  104. Meyer, A., Auernheimer, J., Modlinger, A. & Kessler, H. Targeting RGD recognizing integrins: drug development, biomaterial research, tumor imaging and targeting. Curr. Pharm. Des. 12, 2723–2747 (2006).

    CAS  PubMed  Google Scholar 

  105. Mukherjee, S. et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J. Clin. Invest. 118, 491–504 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Jilka, R. L. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40, 1434–1446 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Compston, J. E. Skeletal actions of intermittent parathyroid hormone: effects on bone remodelling and structure. Bone 40, 1447–1452 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The author's research work discussed in this paper was supported in part by INSERM and University Paris Diderot, the Agence Nationale de la Recherche (grant number ANR-2010-BLAN-1505-01, Integros) and the Fondation de l'Avenir pour la Recherche Appliquée, Paris, France (grant ET9-521). The author thanks Drs G. Tucker and D. Bouvard for their comments, and Z. Saidak for language corrections.

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  1. Unité Mixte de Recherche 606, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    Pierre J. Marie

  2. Hôpital Lariboisière, 2 rue Ambroise Paré, Paris cedex 10, 75475, France

    Pierre J. Marie

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The author declares that he is an inventor on patent application numbers WO2010015938 (A2) WO2010015938 (A3) and EP2328924 (A2).

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Marie, P. Targeting integrins to promote bone formation and repair. Nat Rev Endocrinol 9, 288–295 (2013). https://doi.org/10.1038/nrendo.2013.4

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