[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies

  • Skeletal Biology and Regulation (M Forwood and A Robling, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We reviewed the current literature on the roles of the Wnt antagonists sclerostin (Sost) and sclerostin-containing domain protein 1 (Sostdc1) on bone homeostasis, the relationship of the hypoxia-inducible factor (Hif) and von Hippel-Lindau (Vhl) pathways on Sost expression, and how changes in bone induced by depletion of Sost, Sostdc1, and Vhl affect hematopoietic cells.

Recent Findings

B cell development is adversely affected in Sost-knockout mice and is more severely affected in Vhl-knockout mice. Inflammation in the Sost−/− bone microenvironment could alter hematopoietic stem cell behavior. Sostdc1−/− mice display defects in natural killer cell development and cytotoxicity.

Summary

Depletion of Sost and Sostdc1 have effects on immune cell function that warrant investigation in patients receiving Wnt antagonist-depleting therapies for treatment of bone diseases. Additional clinical applications for manipulation of Wnt antagonists include cancer immunotherapies, stem cell transplantation, and directed differentiation to immune lineages.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Canalis E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol. 2013;9(10):575–83.

    Article  CAS  PubMed  Google Scholar 

  2. Canalis E. Management of endocrine disease: novel anabolic treatments for osteoporosis. Eur J Endocrinol. 2018;178(2):R33–44.

    Article  CAS  PubMed  Google Scholar 

  3. Langdahl BL, Libanati C, Crittenden DB, Bolognese MA, Brown JP, Daizadeh NS, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet. 2017;390(10102):1585–94.

    Article  CAS  PubMed  Google Scholar 

  4. Richter J, Traver D, Willert K. The role of Wnt signaling in hematopoietic stem cell development. Crit Rev Biochem Mol Biol. 2017;52(4):414–24.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cain CJ, Manilay JO. Hematopoietic stem cell fate decisions are regulated by Wnt antagonists: comparisons and current controversies. Exp Hematol. 2013;41(1):3–16.

    Article  CAS  PubMed  Google Scholar 

  6. Laurikkala J, Kassai Y, Pakkasjarvi L, Thesleff I, Itoh N. Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Dev Biol. 2003;264(1):91–105.

    Article  CAS  PubMed  Google Scholar 

  7. Ahn Y, Sanderson BW, Klein OD, Krumlauf R. Inhibition of Wnt signaling by wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development. 2010;137(19):3221–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. •• Collette NM, Yee CS, Hum NR, Murugesh DK, Christiansen BA, Xie L, et al. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells. Bone. 2016;88:20–30 This study used genetic knockout mice to outline the role of Sostdc1 as a negative regulator of bone fracture repair and identified Sostdc1 expression in periosteal cells and MSCs and their role in bone fracture repair. Furthermore, Sostdc1−/− mice were found to have enlarged cortical bones with higher bone marrow density.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. •• Millan A, Elizaldi S, Lee E, Aceves J, Murugesh D, L GG, et al. Sostdc1 regulates natural killer cell maturation and cytotoxicity. J. of Immunology, 2019, in press This study demonstrates that Sostdc1 plays a crucial role in NK cell maturation and cytotoxicity, and reveals Sostdc1 from both hematopoietic and non-hematopoietic sources differentially regulate on NK cell development.

  10. • Georgiev H, Ravens I, Papadogianni G, Halle S, Malissen B, Loots GG, et al. Shared and unique features distinguishing follicular T helper and regulatory cells of peripheral lymph node and Peyer’s Patches. Front Immunol. 2018;9:714 This study found Sostdc1 expression in CD4 + T follicular helper (T FH ) and T follicular regulatory (T FR ) cells in the peripheral lymph node and Peyer’s Patches, and revealed that lack of Sostdc1 in mice increases frequencies of memory B cells increases fecal IgA secretion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shimatani K, Nakashima Y, Hattori M, Hamazaki Y, Minato N. PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia. Proc Natl Acad Sci U S A. 2009;106(37):15807–12.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cain CJ, Rueda R, McLelland B, Collette NM, Loots GG, Manilay JO. Absence of sclerostin adversely affects B-cell survival. J Bone Miner Res. 2012;27(7):1451–61.

    Article  CAS  PubMed  Google Scholar 

  13. Chow A, Mason J, Coney L, Bajwa J, Zaslavsky A, Pellman Y, et al. Sclerostin deficiency alters peripheral B lymphocyte responses in mice. BioRxiv 2018. https://doi.org/10.1101/357772.

  14. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. You L, Chen L, Pan L, Peng Y, Chen J. SOST gene inhibits osteogenesis from adipose-derived mesenchymal stem cells by inducing Th17 cell differentiation. Cell Physiol Biochem. 2018;48(3):1030–40.

    Article  CAS  PubMed  Google Scholar 

  16. Divieti Pajevic P, Krause DS. Osteocyte regulation of bone and blood. Bone. 2019;119:13–18.

  17. Kobayashi Y, Thirukonda GJ, Nakamura Y, Koide M, Yamashita T, Uehara S, et al. Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a. Biochem Biophys Res Commun. 2015;463(4):1278–83.

    Article  CAS  PubMed  Google Scholar 

  18. Chae W-J, Bothwell A. Canonical and non-canonical Wnt signaling in immune cells. Trends Immunol. 2018. https://doi.org/10.1016/j.it.2018.08.006.

  19. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, et al. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008;10(10):1208–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhong Z, Zylstra-Diegel CR, Schumacher CA, Baker JJ, Carpenter AC, Rao S, et al. Wntless functions in mature osteoblasts to regulate bone mass. Proc Natl Acad Sci U S A. 2012;109(33):E2197–204.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhong Z, Ethen NJ, Williams BO. WNT signaling in bone development and homeostasis. Wiley Interdiscip Rev Dev Biol. 2014;3(6):489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leucht P, Lee S, Yim N. Wnt signaling and bone regeneration: can’t have one without the other. Biomaterials. 2018.

  23. Mazumdar J, O'Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS, et al. O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol. 2010;12(10):1007–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Newton IP, Kenneth NS, Appleton PL, Nathke I, Rocha S. Adenomatous polyposis coli and hypoxia-inducible factor-1{alpha} have an antagonistic connection. Mol Biol Cell. 2010;21(21):3630–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol. 2007;9(2):210–7.

    Article  CAS  PubMed  Google Scholar 

  26. Iqbal S, Zhang S, Driss A, Liu ZR, Kim HR, Wang Y, et al. PDGF upregulates Mcl-1 through activation of beta-catenin and HIF-1alpha-dependent signaling in human prostate cancer cells. PLoS One. 2012;7(1):e30764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood. 2008;111(2):492–503.

    Article  CAS  PubMed  Google Scholar 

  28. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423(6938):409–14.

    Article  CAS  PubMed  Google Scholar 

  29. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, et al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006;7(10):1037–47.

    Article  CAS  PubMed  Google Scholar 

  30. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol. 2006;7(10):1048–56.

    Article  CAS  PubMed  Google Scholar 

  31. Staal FJ, Chhatta A, Mikkers H. Caught in a Wnt storm: complexities of Wnt signaling in hematopoiesis. Exp Hematol. 2016;44(6):451–7.

    Article  CAS  PubMed  Google Scholar 

  32. Famili F, Naber BA, Vloemans S, de Haas EF, Tiemessen MM, Staal FJ. Discrete roles of canonical and non-canonical Wnt signaling in hematopoiesis and lymphopoiesis. Cell Death Dis. 2015;6:e1981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McClung MR. Sclerostin antibodies in osteoporosis: latest evidence and therapeutic potential. Ther Adv Musculoskelet Dis. 2017;9(10):263–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860–9.

    Article  PubMed  Google Scholar 

  35. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res. 2007;22(1):19–28.

    Article  PubMed  Google Scholar 

  36. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842–4.

    Article  CAS  PubMed  Google Scholar 

  37. Gori F, Lerner U, Ohlsson C, Baron R. A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures. Bonekey Rep. 2015;4:669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286(22):19489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280(29):26770–5.

    Article  CAS  PubMed  Google Scholar 

  40. Tu X, Delgado-Calle J, Condon KW, Maycas M, Zhang H, Carlesso N, et al. Osteocytes mediate the anabolic actions of canonical Wnt/beta-catenin signaling in bone. Proc Natl Acad Sci U S A. 2015;112(5):E478–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bouaziz W, Funck-Brentano T, Lin H, Marty C, Ea HK, Hay E, et al. Loss of sclerostin promotes osteoarthritis in mice via beta-catenin-dependent and -independent Wnt pathways. Arthritis Res Ther. 2015;17:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. •• Yee CS, Manilay JO, Chang JC, Hum NR, Murugesh DK, Bajwa J, et al. Conditional deletion of Sost in MSC-derived lineages identifies specific cell type contributions to bone mass and B cell development. J Bone Miner Res. 2018;33(10):1748–59 This study utilized conditional Sost knockout mice to reveal novel roles of mesenchymal stem cells in control of bone homeostasis and B cell development and revealed that osteocyte specific Sost is not the main driver of these processes.

    Article  CAS  PubMed  Google Scholar 

  43. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39(2):91–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. van Lierop AH, Hamdy NA, van Egmond ME, Bakker E, Dikkers FG, Papapoulos SE. Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res. 2013;28(4):848–54.

    Article  CAS  PubMed  Google Scholar 

  45. Nassar K, Rachidi W, Janani S, Mkinsi O. Van Buchem’s disease. Joint Bone Spine. 2016;83(6):737–8.

    Article  PubMed  Google Scholar 

  46. Kageyama Y, Koshiji M, To KK, Tian YM, Ratcliffe PJ, Huang LE. Leu-574 of human HIF-1alpha is a molecular determinant of prolyl hydroxylation. FASEB J. 2004;18(9):1028–30.

    Article  CAS  PubMed  Google Scholar 

  47. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393–402.

    Article  CAS  PubMed  Google Scholar 

  48. Wang V, Davis DA, Haque M, Huang LE, Yarchoan R. Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res. 2005;65(8):3299–306.

    Article  CAS  PubMed  Google Scholar 

  49. Liao SH, Zhao XY, Han YH, Zhang J, Wang LS, Xia L, et al. Proteomics-based identification of two novel direct targets of hypoxia-inducible factor-1 and their potential roles in migration/invasion of cancer cells. Proteomics. 2009;9(15):3901–12.

    Article  CAS  PubMed  Google Scholar 

  50. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Riddle RC, Khatri R, Schipani E, Clemens TL. Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. J Mol Med (Berl). 2009;87(6):583–90.

    Article  CAS  Google Scholar 

  52. Lu C, Saless N, Wang X, Sinha A, Decker S, Kazakia G, et al. The role of oxygen during fracture healing. Bone. 2013;52(1):220–9.

    Article  CAS  PubMed  Google Scholar 

  53. Hirao M, Hashimoto J, Yamasaki N, Ando W, Tsuboi H, Myoui A, et al. Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes. J Bone Miner Metab. 2007;25(5):266–76.

    Article  CAS  PubMed  Google Scholar 

  54. Knowles HJ. Hypoxic regulation of osteoclast differentiation and bone resorption activity. Hypoxia (Auckl). 2015;3:73–82.

    Article  Google Scholar 

  55. Komatsu DE, Hadjiargyrou M. Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. Bone. 2004;34(4):680–8.

    Article  CAS  PubMed  Google Scholar 

  56. Danis A. Mechanism of bone lengthening by the Ilizarov technique. Bull Mem Acad R Med Belg. 2001;156(1–2):107–12.

    CAS  PubMed  Google Scholar 

  57. Zhao Q, Shen X, Zhang W, Zhu G, Qi J, Deng L. Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss. Bone. 2012;50(3):763–70.

    Article  CAS  PubMed  Google Scholar 

  58. Tando T, Sato Y, Miyamoto K, Morita M, Kobayashi T, Funayama A, et al. Hif1alpha is required for osteoclast activation and bone loss in male osteoporosis. Biochem Biophys Res Commun. 2016;470(2):391–6.

    Article  CAS  PubMed  Google Scholar 

  59. Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, et al. HIF1alpha is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc Natl Acad Sci U S A. 2013;110(41):16568–73.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Weng T, Xie Y, Huang J, Luo F, Yi L, He Q, et al. Inactivation of Vhl in osteochondral progenitor cells causes high bone mass phenotype and protects against age-related bone loss in adult mice. J Bone Miner Res. 2014;29(4):820–9.

    Article  CAS  PubMed  Google Scholar 

  61. Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert SR, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117(6):1616–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wan C, Gilbert SR, Wang Y, Cao X, Shen X, Ramaswamy G, et al. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A. 2008;105(2):686–91.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zuo GL, Zhang LF, Qi J, Kang H, Jia P, Chen H, et al. Activation of HIFa pathway in mature osteoblasts disrupts the integrity of the osteocyte/canalicular network. PLoS One. 2015;10(3):e0121266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. •• Loots GG, Robling AG, Chang JC, Murugesh DK, Bajwa J, Carlisle C, et al. Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects. Bone. 2018;116:307–14 The findings in this article highlight the VHL and HIF influences in skeletal development and repair. It has an additional focus on the implications in the immune system in particular of B cell development.

    Article  CAS  PubMed  Google Scholar 

  65. Chen D, Li Y, Zhou Z, Wu C, Xing Y, Zou X, et al. HIF-1alpha inhibits Wnt signaling pathway by activating Sost expression in osteoblasts. PLoS One. 2013;8(6):e65940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. • Stegen S, Stockmans I, Moermans K, Thienpont B, Maxwell PH, Carmeliet P, et al. Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin. Nat Commun. 2018;9(1):2557 This article revealed the role of PHD2 role in the bone homeostasis through epigenetic regulation of sclerostin expression through the Wnt signaling pathway, and a possible strategy to treat osteoporosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Genetos DC, Toupadakis CA, Raheja LF, Wong A, Papanicolaou SE, Fyhrie DP, et al. Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem. 2010;110(2):457–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wu JY, Scadden DT, Kronenberg HM. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J Bone Miner Res. 2009;24(5):759–64.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007;104(13):5431–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508(7495):269–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bader HL, Hsu T. Systemic VHL gene functions and the VHL disease. FEBS Lett. 2012;586(11):1562–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature. 2016;537(7619):234–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Togo Y, Takahashi K, Saito K, Kiso H, Tsukamoto H, Huang B, et al. Antagonistic functions of USAG-1 and RUNX2 during tooth development. PLoS One. 2016;11(8):e0161067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kiso H, Takahashi K, Saito K, Togo Y, Tsukamoto H, Huang B, et al. Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations. PLoS One. 2014;9(5):e96938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Collette NM, Yee CS, Murugesh D, Sebastian A, Taher L, Gale NW, et al. Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Dev Biol. 2013;383(1):90–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tanaka M, Endo S, Okuda T, Economides AN, Valenzuela DM, Murphy AJ, et al. Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney development and injury. Kidney Int. 2008;73(2):181–91.

    Article  CAS  PubMed  Google Scholar 

  77. Manilay JO, Waneck GL, Sykes M. Altered expression of Ly-49 receptors on NK cells developing in mixed allogeneic bone marrow chimeras. Int Immunol. 1998;10(12):1943–55.

    Article  CAS  PubMed  Google Scholar 

  78. Tu MM, Mahmoud AB, Makrigiannis AP. Licensed and unlicensed NK cells: differential roles in cancer and viral control. Front Immunol. 2016;7:166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 2009;136(6):1136–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012;18(12):1778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476(7360):293–7.

    Article  CAS  PubMed  Google Scholar 

  82. Liu D, He XC, Qian P, Barker N, Trainor PA, Clevers H, et al. Leucine-rich repeat-containing G-protein-coupled receptor 5 marks short-term hematopoietic stem and progenitor cells during mouse embryonic development. J Biol Chem. 2014;289(34):23809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sugimura R, He XC, Venkatraman A, Arai F, Box A, Semerad C, et al. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell. 2012;150(2):351–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Florian MC, Nattamai KJ, Dorr K, Marka G, Uberle B, Vas V, et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature. 2013;503(7476):392–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. • Himburg HA, Doan PL, Quarmyne M, Yan X, Sasine J, Zhao L, et al. Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med. 2017;23(1):91–9 This study showed that secretion of Dkk1 by BM osteoprogenitors regulates promotes hematopoietic regeneration directly through inhibition of HSC quiescence as well as indirectly through EGF secretion by BM endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  86. Witcher PC, Miner SE, Horan DJ, Bullock WA, Lim KE, Kang KS, et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight. 2018;3(11).

  87. Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun. 2016;7:11505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(2):181–92 e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang B, Tian T, Kalland KH, Ke X, Qu Y. Targeting Wnt/beta-catenin signaling for cancer immunotherapy. Trends Pharmacol Sci. 2018;39(7):648–58.

    Article  CAS  PubMed  Google Scholar 

  90. Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. 2009;15(7):808–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gajewski TF, Corrales L, Williams J, Horton B, Sivan A, Spranger S. Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment. Adv Exp Med Biol. 2017;1036:19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Regan JN, Lim J, Shi Y, Joeng KS, Arbeit JM, Shohet RV, et al. Up-regulation of glycolytic metabolism is required for HIF1alpha-driven bone formation. Proc Natl Acad Sci U S A. 2014;111(23):8673–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li Z, Frey JL, Wong GW, Faugere MC, Wolfgang MJ, Kim JK, et al. Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts. Endocrinology. 2016;157(11):4094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Esen E, Long F. Aerobic glycolysis in osteoblasts. Curr Osteoporos Rep. 2014;12(4):433–8.

    Article  PubMed  PubMed Central  Google Scholar 

  95. •• Dirckx N, Tower RJ, Mercken EM, Vangoitsenhoven R, Moreau-Triby C, Breugelmans T, et al. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. J Clin Invest. 2018;128(3):1087–105 The findings in this article indicate important metabolic regulation in osteoblasts can extend beyond the bone environment. It showed that deleting VHL in osteoblast cells alters metabolic homeostasis through the VHL/HIF pathway. This highlights the skeleton’s role in global nutrient homeostasis.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Krzywinska E, Stockmann C. Hypoxia, metabolism and immune cell function. Biomedicines. 2018;6(2):56.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Damian Genetos and Dr. Gabriela Loots for their comments on the manuscript.

Funding

This work was supported by University of California (UC), Merced faculty research funding, University of California Cancer Research Coordinating Committee Grant CRC-15-380532, National Institutes of Health Award 1R15HL121786-01A1, Halcyon-Dixon Trust award to JOM, and UC Graduate Student Fellowships to AM, CD, and BC.

Author information

Author notes

  1. Betsabel Chicana, Cristine Donham, and Alberto J. Millan contributed equally to the writing of this article.

Authors and Affiliations

  1. Quantitative and Systems Biology Graduate Program, University of California, Merced, CA, USA

    Betsabel Chicana, Cristine Donham, Alberto J. Millan & Jennifer O. Manilay

  2. Department of Molecular and Cell Biology, School of Natural Sciences, University of California, 5200 North Lake Road, Merced, CA, 95343, USA

    Jennifer O. Manilay

Authors
  1. Betsabel Chicana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristine Donham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto J. Millan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer O. Manilay
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Drafting and revising manuscript: BC, CD, AM and JOM; approving final version of manuscript: JOM.

Corresponding author

Correspondence to Jennifer O. Manilay.

Ethics declarations

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards and institutional approvals.

Conflict of Interest

Betsabel Chicana, Cristine, Alberto Millan, and Jennifer Manilay declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Skeletal Biology and Regulation

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chicana, B., Donham, C., Millan, A.J. et al. Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies. Curr Osteoporos Rep 17, 49–58 (2019). https://doi.org/10.1007/s11914-019-00503-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-019-00503-3

Keywords

Search

Navigation