Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression

Nature Cell Biology volume 14, pages 727–737 (2012)Cite this article

Subjects

Abstract

Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1–Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16INK4a. c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16INK4a upregulation and osteoblast senescence. Mouse genetic studies revealed that p16INK4a controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16INK4a expression and osteoprogenitor expansion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: c-A b l−/− osteoblasts show reduced proliferation potential in vivo and undergo premature senescence ex vivo.
Figure 2: c-A b l−/− osteoblasts showed p16INK4a upregulation, which is responsible for premature senescence.
Figure 3: c-A b l−/− osteoblasts show enhanced Erk1/2 activation in response to BMP2, which contributes to p16INK4a upregulation.
Figure 4: c-Abl positively regulates the expression of Id1 through BMP–Smad1/5/8 signalling, which contributes to p16INK4a upregulation.
Figure 5: c-Abl phosphorylates BMPRIA, which plays a role in osteoblast expansion.
Figure 6: c-Abl-mediated BMPRIA phosphorylation negatively regulates Erk1/2 activation but positively regulates Smad1/5/8 activation.
Figure 7: A role for p16INK4a in MSC maintenance and osteoblastogenesis in normal and c-A b l−/− mice.

Similar content being viewed by others

References

  1. Harada, S. & Rodan, G. A. Control of osteoblast function and regulation of bone mass. Nature 423, 349–355 (2003).

    Article  CAS  Google Scholar 

  2. Olsen, B. R., Reginato, A. M. & Wang, W. Bone development. Annu. Rev. Cell Dev. Biol. 16, 191–220 (2000).

    Article  CAS  Google Scholar 

  3. Ducy, P., Schinke, T. & Karsenty, G. The osteoblast: a sophisticated fibroblast under central surveillance. Science 289, 1501–1504 (2000).

    Article  CAS  Google Scholar 

  4. Canalis, E., Economides, A. N. & Gazzerro, E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr. Rev. 24, 218–235 (2003).

    Article  CAS  Google Scholar 

  5. Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J Clin. Invest. 113, 160–168 (2004).

    Article  CAS  Google Scholar 

  6. Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock? Cell 102, 407–410 (2000).

    Article  CAS  Google Scholar 

  7. Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001).

    Article  CAS  Google Scholar 

  8. Ivanov, A. & Adams, P. D. A damage limitation exercise. Nat. Cell Biol. 13, 193–195 (2011).

    Article  CAS  Google Scholar 

  9. Lundberg, A. S., Hahn, W. C., Gupta, P. & Weinberg, R. A. Genes involved in senescence and immortalization. Curr. Opin. Cell Biol. 12, 705–709 (2000).

    Article  CAS  Google Scholar 

  10. Takahashi, A. et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8, 1291–1297 (2006).

    Article  CAS  Google Scholar 

  11. Schmitt, C. A. Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat. Rev. Cancer 3, 286–295 (2003).

    Article  CAS  Google Scholar 

  12. Beausejour, C. M. & Campisi, J. Ageing: balancing regeneration and cancer. Nature 443, 404–405 (2006).

    Article  CAS  Google Scholar 

  13. Van Riggelen, J. & Felsher, D. W. Myc and a Cdk2 senescence switch. Nat. Cell Biol. 12, 7–9 (2010).

    Article  CAS  Google Scholar 

  14. Van Etten, R. A. Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol. 9, 179–186 (1999).

    Article  CAS  Google Scholar 

  15. Hantschel, O. & Superti-Furga, G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat. Rev. Mol. Cell Biol. 5, 33–44 (2004).

    Article  CAS  Google Scholar 

  16. Wong, S. & Witte, O. N. The BCR-ABL story: bench to bedside and back. Annu. Rev. Immunol. 22, 247–306 (2004).

    Article  CAS  Google Scholar 

  17. Pendergast, A. M. The Abl family kinases: mechanisms of regulation and signaling. Adv. Cancer Res. 85, 51–100 (2002).

    Article  CAS  Google Scholar 

  18. Wang, X. et al. A positive role for c-Abl in Atm and Atr activation in DNA damage response. Cell Death Diff. 18, 5–15 (2011).

    Article  Google Scholar 

  19. Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 (1991).

    Article  CAS  Google Scholar 

  20. Schwartzberg, P. L. et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 65, 1165–1175 (1991).

    Article  CAS  Google Scholar 

  21. Li, B. et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet. 24, 304–308 (2000).

    Article  CAS  Google Scholar 

  22. Li, B. et al. Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. Genes Dev. 18, 1824–1837 (2004).

    Article  CAS  Google Scholar 

  23. Silberman, I. et al. T cell survival and function requires the c- Abl tyrosine kinase. Cell Cycle 7, 3847–3857 (2008).

    Article  CAS  Google Scholar 

  24. Huang, Y. et al. The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse. Blood 112, 111–119 (2008).

    Article  CAS  Google Scholar 

  25. Tzeng, S. J., Bolland, S., Inabe, K., Kurosaki, T. & Pierce, S. K. The B cell inhibitory Fc receptor triggers apoptosis by a novel c-Abl family kinase-dependent pathway. J. Biol. Chem. 280, 35247–35254 (2005).

    Article  CAS  Google Scholar 

  26. Zipfel, P. A., Zhang, W., Quiroz, M. & Pendergast, A. M. Requirement for Abl kinases in T cell receptor signaling. Curr. Biol. 14, 1222–1231 (2004).

    Article  CAS  Google Scholar 

  27. Koleske, A. J. et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21, 1259–1272 (1998).

    Article  CAS  Google Scholar 

  28. Schlatterer, S. D., Acker, C. M. & Davies, P. c-Abl in neurodegenerative disease. J. Mol. Neurosci. 45, 445–452 (2011).

    Article  CAS  Google Scholar 

  29. Ko, H. S. et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc. Natl Acad. Sci. USA 107, 16691–16696 (2010).

    Article  CAS  Google Scholar 

  30. De Arce, K. P. et al. Synaptic clustering of PSD-95 is regulated by c-Abl through tyrosine phosphorylation. J. Neurosci. 30, 3728–3738 (2010).

    Article  Google Scholar 

  31. Michael, M., Vehlow, A., Navarro, C. & Krause, M. c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis. Curr. Biol. 20, 783–791 (2010).

    Article  CAS  Google Scholar 

  32. Woodring, P. J. et al. Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension. J Cell Biol. 156, 879–892 (2002).

    Article  CAS  Google Scholar 

  33. Zukerberg, L. R. et al. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26, 633–646 (2000).

    Article  CAS  Google Scholar 

  34. Wang, J. Y. Controlling Abl: auto-inhibition and co-inhibition? Nat. Cell Biol. 6, 3–7 (2004).

    Article  CAS  Google Scholar 

  35. Chen, D., Zhao, M. & Mundy, G. R. Bone morphogenetic proteins. Growth Factors 22, 233–241 (2004).

    Article  CAS  Google Scholar 

  36. Varga, A. C. & Wrana, J. L. The disparate role of BMP in stem cell biology. Oncogene 24, 5713–5721 (2005).

    Article  CAS  Google Scholar 

  37. Randle, D. H., Zindy, F., Sherr, C. J. & Roussel, M. F. Differential effects of p19(Arf) and p16(Ink4a) loss on senescence of murine bone marrow -derived preB cells and macrophages. Proc. Natl Acad. Sci. USA 98, 9654–9659 (2001).

    Article  CAS  Google Scholar 

  38. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  Google Scholar 

  39. O’Neill, A. J., Cotter, T. G., Russell, J. M. & Gaffney, E. F. Abl expression in human fetal and adult tissues, tumours, and tumour microvessels. J. Pathol. 183, 325–329 (1997).

    Article  Google Scholar 

  40. Kotake, Y. et al. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4α tumor suppressor gene. Genes Dev. 21, 49–54 (2007).

    Article  CAS  Google Scholar 

  41. Bracken, A. P. et al. The Polycomb group proteins bind throughout theINK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).

    Article  CAS  Google Scholar 

  42. Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998).

    Article  CAS  Google Scholar 

  43. Cagnol, S. & Chambard, J. C. ERK and cell death: mechanisms of ERK—induced cell death—apoptosis, autophagy and senescence. FEBS J. 277, 2–21 (2010).

    Article  CAS  Google Scholar 

  44. Von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat. Cell Biol. 11, 1458–1464 (2009).

    Article  CAS  Google Scholar 

  45. Yamaguchi, K. et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J. 18, 179–187 (1999).

    Article  CAS  Google Scholar 

  46. Sorrentino, A. et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199–1207 (2008).

    Article  CAS  Google Scholar 

  47. Miyazono, K. & Miyazawa, K. Id: a target of BMP signaling. Sci. STKE 2002, pe40 (2002).

    PubMed  Google Scholar 

  48. Zhang, Y. & Derynck, R. Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol. 9, 274–279 (1999).

    Article  CAS  Google Scholar 

  49. Zebedee, Z. & Hara, E. Id proteins in cell cycle control and cellular senescence. Oncogene 20, 8317–8325 (2001).

    Article  CAS  Google Scholar 

  50. Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. Trends Cell Biol. 13, 410–418 (2003).

    Article  CAS  Google Scholar 

  51. Zhao, M. et al. Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J. Cell Biol. 157, 1049–1060 (2002).

    Article  CAS  Google Scholar 

  52. Mishina, Y. et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J. Biol. Chem. 279, 27560–27566 (2004).

    Article  CAS  Google Scholar 

  53. Kamiya, N. et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 135, 3801–3811 (2008).

    Article  CAS  Google Scholar 

  54. Kamiya, N. et al. Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J. Bone Miner. Res. 23, 2007–2017 (2008).

    Article  CAS  Google Scholar 

  55. Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231–3244 (2006).

    Article  CAS  Google Scholar 

  56. Usui, M. et al. Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J. Bone Miner. Res. 23, 314–325 (2008).

    Article  CAS  Google Scholar 

  57. Whang, Y. E. et al. c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency. Proc. Natl Acad. Sci. USA 97, 5486–5491 (2000).

    Article  CAS  Google Scholar 

  58. Manolagas, S. C. & Jilka, R. L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 332, 305–311 (1995).

    Article  CAS  Google Scholar 

  59. Huot, T. J. et al. Biallelic mutations in p16(INK4a) confer resistance to Ras-and Ets-induced senescence in human diploid fibroblasts. Mol. Cell Biol. 22, 8135–8143 (2002).

    Article  CAS  Google Scholar 

  60. Alani, R. M., Young, A. Z. & Shifflett, C. B. Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a. Proc. Natl Acad. Sci. USA 98, 7812–7816 (2001).

    Article  CAS  Google Scholar 

  61. Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

    Article  CAS  Google Scholar 

  62. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).

    Article  CAS  Google Scholar 

  63. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    Article  CAS  Google Scholar 

  64. Tsuji, K. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 38, 1424–1429 (2006).

    Article  CAS  Google Scholar 

  65. Chang, J. et al. Inhibition of osteoblastic bone formation by nuclear factor-κB. Nat. Med. 15, 682–689 (2009).

    Article  CAS  Google Scholar 

  66. Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation toNF-κB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009).

    Article  CAS  Google Scholar 

  67. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    Article  CAS  Google Scholar 

  68. Yates, J. R. 3rd, Eng, J. K., McCormack, A. L. & Schieltz, D. Method to correlate tandem mass spectra of modified peptides to amino acid sequences in the protein database. Anal. Chem. 67, 1426–1436 (1995).

    Article  CAS  Google Scholar 

  69. Wang, L.H. et al. pFind 2.0: a software package for peptide and protein identification via tandem mass spectrometry. Rapid Commun. Mass Spec. 21, 2985–2991 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Nur-E-Kamal, Y. Wan and X-H. Sun for helpful discussions, I. H. In, D. Cai, G. C. Hong, L. Soh, J. Lin and T. Cheng for technical assistance, and Novartis, J. Campisi (Buck Institute for Research on Aging, USA), J. Wang (UCSD, USA), A. Koleske (Yale University, USA), X-H. Sun (Oklahoma Medical Research Foundation, USA), C. Cepko (Harvard Medical School, USA), D. Bulavin (IMCB, Singapore) and R. DePinho (University of Texas, MD Anderson Cancer Center, USA) for reagents and mice. S.P.G. is an investigator of Howard Hughes Medical Institute. The work was supported by grants from the Ministry of Science and Technology of China (The National Key Scientific Program (2012CB966901, to B.L.)), the National Natural Science Foundation of China (81130039, 31071229 and 81121001), Shanghai Pujiang Program (10PJ1405000), Changjiang Scholars Program of the Ministry of Education and the Agency for Science, Technology and Research of Singapore.

Author information

Author notes

  1. Sharon Boast

    Present address: Present address: Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK,

  2. Hui-Yi Kua, Huijuan Liu and Wai Fook Leong: These authors contributed equally to this work

Authors and Affiliations

  1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China

    Hui-Yi Kua, Huijuan Liu, Lili Li, Deyong Jia, Gang Ma, James Yeh, Lin He & Baojie Li

  2. Institute of Molecular and Cell Biology, A-Star, 61, Biopolis Drive, Singapore 138673, Singapore

    Hui-Yi Kua, Wai Fook Leong, Yuanyu Hu, Jenny F. L. Chau & Baojie Li

  3. Department of Biochemistry, Yong Loo Lin School of Medicine, Cancer Science Institute of Singapore, MD7, 8 Medical Drive, Singapore 117597, Singapore

    Xueying Wang

  4. Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China

    Ye-Guang Chen

  5. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, USA

    Yuji Mishina

  6. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York 100032, USA

    Sharon Boast & Stephen P. Goff

  7. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

    Li Xia & Guo-Qiang Chen

Authors
  1. Hui-Yi Kua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huijuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wai Fook Leong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lili Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deyong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanyu Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xueying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jenny F. L. Chau
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ye-Guang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuji Mishina
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sharon Boast
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Li Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Guo-Qiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stephen P. Goff
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Baojie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.L. and L.H. conceived the project. H-Y.K., H.L, W.F.L., L.L., D.J., Y.H., X.W., J.F.L.C., J.Y., L.X. and G.M. carried out the experiments. Y-G.C, S.P.G., S.B. and Y. M. contributed the knockout mouse lines and constructs. H.L. and H-Y.K. prepared the figures. B.L., S.P.G., G-Q.C., S.B., L.H. and Y.M. wrote the manuscript.

Corresponding author

Correspondence to Baojie Li.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 2198 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kua, HY., Liu, H., Leong, W. et al. c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. Nat Cell Biol 14, 727–737 (2012). https://doi.org/10.1038/ncb2528

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2528

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing