Skip to main content
Log in

Talking among Ourselves: Paracrine Control of Bone Formation within the Osteoblast Lineage

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

While much research focuses on the range of signals detected by the osteoblast lineage that originate from endocrine influences, or from other cells within the body, there are also multiple interactions that occur within this family of cells. Osteoblasts exist as teams and form extensive communication networks both on, and within, the bone matrix. We provide four snapshots of communication pathways that exist within the osteoblast lineage between different stages of their differentiation, as follows: (1) PTHrP, a factor produced by early osteoblasts that stimulates the activity of more mature bone-forming cells and the most mature osteoblast embedded within the bone matrix, the osteocyte; (2) sclerostin, a secreted factor, released by osteocytes into their extensive communication network to restrict the activity of younger osteoblasts on the bone surface; (3) oncostatin M, a member of the IL-6/gp130 family of cytokines, expressed throughout osteoblast differentiation and acting to stimulate osteoblast activity that works on a different receptor in the mature osteocyte compared to the preosteoblast; and (4) Eph/ephrins, cell-contact-dependent kinases, and the osteoblast-lineage-specific interaction of EphB4 and ephrinB2, which provides a checkpoint for entry to the late stages of osteoblast differentiation and restricts RANKL expression.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403

    CAS  PubMed  Google Scholar 

  2. Bianco P, Robey PG, Simmons PJ (2008) Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2:313–319

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13:1025–1036

    CAS  PubMed  Google Scholar 

  4. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    CAS  PubMed  Google Scholar 

  5. Ecarot-Charrier B, Glorieux FH, van der Rest M, Pereira G (1983) Osteoblasts isolated from mouse calvaria initiate matrix mineralization in culture. J Cell Biol 96:639–643

    CAS  PubMed  Google Scholar 

  6. Abe Y, Akamine A, Aida Y, Maeda K (1993) Differentiation and mineralization in osteogenic precursor cells derived from fetal rat mandibular bone. Calcif Tissue Int 52:365–371

    CAS  PubMed  Google Scholar 

  7. Gerber I, ap Gwynn I (2001) Influence of cell isolation, cell culture density, and cell nutrition on differentiation of rat calvarial osteoblast-like cells in vitro. Eur Cell Mater 2:10–20

    CAS  PubMed  Google Scholar 

  8. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764

    CAS  PubMed  Google Scholar 

  9. Aubin JE, Liu F, Malaval L, Gupta AK (1995) Osteoblast and chondroblast differentiation. Bone 17:77S–83S

    CAS  PubMed  Google Scholar 

  10. Sims NA, White CP, Sunn KL, Thomas GP, Drummond ML, Morrison NA, Eisman JA, Gardiner EM (1997) Human and murine osteocalcin gene expression: conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D3 in vivo. Mol Endocrinol 11:1695–1708

    CAS  PubMed  Google Scholar 

  11. Aubin JE (2001) Regulation of osteoblast formation and function. Rev Endocr Metab Disord 2:81–94

    CAS  PubMed  Google Scholar 

  12. Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N, Komori T (2001) Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. J Bone Miner Res 16:2017–2026

    CAS  PubMed  Google Scholar 

  13. Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, Simmons HA, Crawford DT, Chidsey-Frink KL, Ke HZ, McNeish JD, Brown TA (2003) Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J Biol Chem 278:1998–2007

    CAS  PubMed  Google Scholar 

  14. van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Lowik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

    PubMed Central  PubMed  Google Scholar 

  15. Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge EM, Plesner T, Delaisse JM (2009) A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 174:239–247

    CAS  PubMed  Google Scholar 

  16. Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY et al (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896

    CAS  PubMed  Google Scholar 

  17. Grill V, Hillary J, Ho PM, Law FM, MacIsaac RJ, MacIsaac IA, Moseley JM, Martin TJ (1992) Parathyroid hormone-related protein: a possible endocrine function in lactation. Clin Endocrinol 37:405–410

    CAS  Google Scholar 

  18. Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM (1996) Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 93:15233–15238

    CAS  PubMed  Google Scholar 

  19. Strewler GJ (2000) The physiology of parathyroid hormone–related protein. N Engl J Med 342:177–185

    CAS  PubMed  Google Scholar 

  20. Moseley JM, Hayman JA, Danks JA, Alcorn D, Grill V, Southby J, Horton MA (1991) Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia. J Clin Endocrinol Metab 73:478–484

    CAS  PubMed  Google Scholar 

  21. Suda N, Gillespie MT, Traianedes K, Zhou H, Ho PW, Hards DK, Allan EH, Martin TJ, Moseley JM (1996) Expression of parathyroid hormone-related protein in cells of osteoblast lineage. J Cell Physiol 166:94–104

    CAS  PubMed  Google Scholar 

  22. Kartsogiannis V, Moseley J, McKelvie B, Chou ST, Hards DK, Ng KW, Martin TJ, Zhou H (1997) Temporal expression of PTHrP during endochondral bone formation in mouse and intramembranous bone formation in an in vivo rabbit model. Bone 21:385–392

    CAS  PubMed  Google Scholar 

  23. Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM et al (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026

    CAS  PubMed  Google Scholar 

  24. Martin TJ (2005) Osteoblast-derived PTHrP is a physiological regulator of bone formation. J Clin Invest 115:2322–2324

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, Karaplis AC (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1–34. J Clin Invest 115:2402–2411

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Amizuka N, Karaplis AC, Henderson JE, Warshawsky H, Lipman ML, Matsuki Y, Ejiri S, Tanaka M, Izumi N, Ozawa H, Goltzman D (1996) Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol 175:166–176

    CAS  PubMed  Google Scholar 

  27. Carpio L, Gladu J, Goltzman D, Rabbani SA (2001) Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. Am J Physiol Endocrinol Metab 281:E489–E499

    CAS  PubMed  Google Scholar 

  28. Martin TJ, Sims NA (2013) Integrating endocrine and paracrine influences on bone: lessons from parathyroid hormone and parathyroid hormone-related protein. In: Thakker RW, Whyte MP, Eisman JA, Igarashi T (eds) Genetics of bone biology and skeletal disease. Academic Press, New York, pp 53–68

    Google Scholar 

  29. McCauley LK, Martin TJ (2012) Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27:1231–1239

    CAS  PubMed  Google Scholar 

  30. Kronenberg HM (2006) PTHrP and skeletal development. Ann N Y Acad Sci 1068:1–13

    CAS  PubMed  Google Scholar 

  31. Mak KK, Bi Y, Wan C, Chuang PT, Clemens T, Young M, Yang Y (2008) Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression. Dev Cell 14:674–688

    CAS  PubMed  Google Scholar 

  32. Johnson RW, Nguyen MP, Padalecki SS, Grubbs BG, Merkel AR, Oyajobi BO, Matrisian LM, Mundy GR, Sterling JA (2011) TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res 71:822–831

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Sterling JA, Oyajobi BO, Grubbs B, Padalecki SS, Munoz SA, Gupta A, Story B, Zhao M, Mundy GR (2006) The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res 66:7548–7553

    CAS  PubMed  Google Scholar 

  34. Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Juppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666

    CAS  PubMed  Google Scholar 

  35. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–622

    CAS  PubMed  Google Scholar 

  36. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    CAS  PubMed  Google Scholar 

  37. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P, Papapoulos S, Hamersma H, Brunkow ME (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12–q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152

    PubMed  Google Scholar 

  39. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

    CAS  PubMed  Google Scholar 

  40. Loots GG, Kneissel M, Keller H, Baptist M, Chang J, Collette NM, Ovcharenko D, Plajzer-Frick I, Rubin EM (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in van Buchem disease. Genome Res 15:928–935

    CAS  PubMed  Google Scholar 

  41. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844

    CAS  PubMed  Google Scholar 

  42. Sims NA, Chia LY (2012) Regulation of sclerostin expression by paracrine and endocrine factors. Clin Rev Bone Miner Metab 10:98–107

    CAS  Google Scholar 

  43. Didangelos A, Yin X, Mandal K, Baumert M, Jahangiri M, Mayr M (2010) Proteomics characterization of extracellular space components in the human aorta. Mol Cell Proteomics 9:2048–2062

    CAS  PubMed  Google Scholar 

  44. Modder UI, Clowes JA, Hoey K, Peterson JM, McCready L, Oursler MJ, Riggs BL, Khosla S (2011) Regulation of circulating sclerostin levels by sex steroids in women and in men. J Bone Miner Res 26:27–34

    CAS  PubMed  Google Scholar 

  45. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869

    PubMed  Google Scholar 

  46. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 24:1651–1661

    CAS  PubMed  Google Scholar 

  47. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (2006) Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171 V to modulate Wnt activity. J Bone Miner Res 21:1738–1749

    CAS  PubMed  Google Scholar 

  48. Balemans W, Piters E, Cleiren E, Ai M, Van Wesenbeeck L, Warman ML, Van Hul W (2008) The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int 82:445–453

    CAS  PubMed  Google Scholar 

  49. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887

    CAS  PubMed  Google Scholar 

  50. Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775

    CAS  PubMed  Google Scholar 

  51. Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, Bouwmeester T, Schirle M, Bueno-Lozano M, Fuentes FJ, Itin PH, Boudin E, de Freitas F, Jennes K, Brannetti B, Charara N, Ebersbach H, Geisse S, Lu CX, Bauer A, Van Hul W, Kneissel M (2011) Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 286:19489–19500

    CAS  PubMed  Google Scholar 

  52. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192

    CAS  PubMed  Google Scholar 

  53. Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG (2011) Lrp5 functions in bone to regulate bone mass. Nat Med 17:684–691

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Xiao Z, Dallas M, Qiu N, Nicolella D, Cao L, Johnson M, Bonewald L, Quarles LD (2011) Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J 25:2418–2432

    CAS  PubMed  Google Scholar 

  56. Hens JR, Wilson KM, Dann P, Chen X, Horowitz MC, Wysolmerski JJ (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103–1113

    CAS  PubMed  Google Scholar 

  57. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875

    CAS  PubMed  Google Scholar 

  58. Tian X, Jee WS, Li X, Paszty C, Ke HZ (2011) Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone 48:197–201

    CAS  PubMed  Google Scholar 

  59. Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, Ferrari SL (2009) The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem 284:35939–35950

    CAS  PubMed  Google Scholar 

  60. Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425–1436

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, Gillespie MT, Martin TJ, Sims NA (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J Clin Invest 120:582–592

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Genetos DC, Yellowley CE, Loots GG (2011) Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PLoS One 6:e17772

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Genetos DC, Toupadakis CA, Raheja LF, Wong A, Papanicolaou SE, Fyhrie DP, Loots GG, Yellowley CE (2010) Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem 110:457–467

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Yang F, Tang W, So S, de Crombrugghe B, Zhang C (2010) Sclerostin is a direct target of osteoblast-specific transcription factor osterix. Biochem Biophys Res Commun 400:684–688

    CAS  PubMed  Google Scholar 

  65. Kramer I, Keller H, Leupin O, Kneissel M (2010) Does osteocytic SOST suppression mediate PTH bone anabolism? Trends Endocrinol Metab 21:237–244

    CAS  PubMed  Google Scholar 

  66. Sims NA (2010) Building bone with a SOST–PTH partnership. J Bone Miner Res 25:175–177

    CAS  PubMed  Google Scholar 

  67. Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158

    CAS  PubMed  Google Scholar 

  68. Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583

    CAS  PubMed  Google Scholar 

  69. Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2010) Parathyroid hormone (PTH) induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 25:178–189

    CAS  PubMed  Google Scholar 

  70. Robling AG, Kedlaya R, Ellis SN, Childress PJ, Bidwell JP, Bellido T, Turner CH (2011) Anabolic and catabolic regimens of human parathyroid hormone 1–34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 152:2963–2975

    CAS  PubMed  Google Scholar 

  71. Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21–32

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T, Kishimoto T, Suda T (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA 90:11924–11928

    CAS  PubMed  Google Scholar 

  73. Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP (2006) Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 54:158–168

    CAS  PubMed  Google Scholar 

  74. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan GA, Costantini F (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 13:1189–1196

    CAS  PubMed  Google Scholar 

  75. Metcalf D, Gearing DP (1989) Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. Proc Natl Acad Sci USA 86:5948–5952

    CAS  PubMed  Google Scholar 

  76. Sims NA, Walsh NC (2010) GP130 cytokines and bone remodelling in health and disease. BMB Rep 43:513–523

    CAS  PubMed  Google Scholar 

  77. Sims NA, Johnson RW (2012) Leukemia inhibitory factor: a paracrine mediator of bone metabolism. Growth Factors 30:76–87

    CAS  PubMed  Google Scholar 

  78. Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS, Cosman D (1996) Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem 271:32635–32643

    CAS  PubMed  Google Scholar 

  79. Ichihara M, Hara T, Kim H, Murate T, Miyajima A (1997) Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood 90:165–173

    CAS  PubMed  Google Scholar 

  80. Fu Q, Jilka RL, Manolagas SC, O’Brien CA (2002) Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem 277:48868–48875

    CAS  PubMed  Google Scholar 

  81. Kim S, Yamazaki M, Shevde NK, Pike JW (2007) Transcriptional control of receptor activator of nuclear factor-kappaB ligand by the protein kinase A activator forskolin and the transmembrane glycoprotein 130-activating cytokine, oncostatin M, is exerted through multiple distal enhancers. Mol Endocrinol 21:197–214

    CAS  PubMed  Google Scholar 

  82. Walker EC, McGregor NE, Poulton IJ, Pompolo S, Allan EH, Quinn JM, Gillespie MT, Martin TJ, Sims NA (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res 23:2025–2032

    CAS  PubMed  Google Scholar 

  83. Poulton IJ, McGregor NE, Pompolo S, Walker EC, Sims NA (2012) Contrasting roles of LIF in murine bone development and remodeling involve region-specific changes in vascularization. J Bone Miner Res 27:902–912

    PubMed  Google Scholar 

  84. McGregor NE, Poulton IJ, Walker EC, Pompolo S, Quinn JM, Martin TJ, Sims NA (2010) Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling. Calcif Tissue Int 86:261–270

    CAS  PubMed  Google Scholar 

  85. Greenfield EM, Gornik SA, Horowitz MC, Donahue HJ, Shaw SM (1993) Regulation of cytokine expression in osteoblasts by parathyroid hormone: rapid stimulation of interleukin-6 and leukemia inhibitory factor mRNA. J Bone Miner Res 8:1163–1171

    CAS  PubMed  Google Scholar 

  86. Walker EC, Poulton IJ, McGregor NE, Ho PW, Allan EH, Quach JM, Martin TJ, Sims NA (2012) Sustained RANKL response to parathyroid hormone in oncostatin M receptor-deficient osteoblasts converts anabolic treatment to a catabolic effect in vivo. J Bone Miner Res 27:902–912

    CAS  PubMed  Google Scholar 

  87. Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T, Hilton DJ, Suda T, Ng KW, Martin TJ (1996) The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J Exp Med 183:2581–2591

    CAS  PubMed  Google Scholar 

  88. Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987) A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238:1717–1720

    CAS  PubMed  Google Scholar 

  89. Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90:403–404

    Google Scholar 

  90. Pasquale EB (2008) Eph–ephrin bidirectional signaling in physiology and disease. Cell 133:38–52

    CAS  PubMed  Google Scholar 

  91. Murai KK, Pasquale EB (2003) ‘Eph’ective signaling: forward, reverse and crosstalk. J Cell Sci 116:2823–2832

    CAS  PubMed  Google Scholar 

  92. Irie N, Takada Y, Watanabe Y, Matsuzaki Y, Naruse C, Asano M, Iwakura Y, Suda T, Matsuo K (2009) Bidirectional signaling through ephrinA2–EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem 284:14637–14644

    CAS  PubMed  Google Scholar 

  93. Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K (2006) Bidirectional ephrinB2–EphB4 signaling controls bone homeostasis. Cell Metab 4:111–121

    CAS  PubMed  Google Scholar 

  94. Ting MC, Wu NL, Roybal PG, Sun J, Liu L, Yen Y, Maxson RE Jr (2009) EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis. Development 136:855–864

    CAS  PubMed  Google Scholar 

  95. Merrill AE, Bochukova EG, Brugger SM, Ishii M, Pilz DT, Wall SA, Lyons KM, Wilkie AO, Maxson RE Jr (2006) Cell mixing at a neural crest–mesoderm boundary and deficient ephrin–Eph signaling in the pathogenesis of craniosynostosis. Hum Mol Genet 15:1319–1328

    CAS  PubMed  Google Scholar 

  96. Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, Adams RH, Wieacker P (2004) Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74:1209–1215

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Davy A, Bush JO, Soriano P (2006) Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol 4:e315

    PubMed Central  PubMed  Google Scholar 

  98. Xing W, Kim J, Wergedal J, Chen ST, Mohan S (2010) Ephrin B1 regulates bone marrow stromal cell differentiation and bone formation by influencing TAZ transactivation via complex formation with NHERF1. Mol Cell Biol 30:711–721

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7:501–509

    CAS  PubMed  Google Scholar 

  100. Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB (2001) Crystal structure of an Eph receptor–ephrin complex. Nature 414:933–938

    CAS  PubMed  Google Scholar 

  101. Allan EH, Hausler KD, Wei T, Gooi JH, Quinn JM, Crimeen-Irwin B, Pompolo S, Sims NA, Gillespie MT, Onyia JE, Martin TJ (2008) EphrinB2 regulation by PTH and PTHrP revealed by molecular profiling in differentiating osteoblasts. J Bone Miner Res 23:1170–1181

    CAS  PubMed  Google Scholar 

  102. Martin TJ, Allan EH, Ho PW, Gooi JH, Quinn JM, Gillespie MT, Krasnoperov V, Sims NA (2010) Communication between ephrinB2 and EphB4 within the osteoblast lineage. Adv Exp Med Biol 658:51–60

    CAS  PubMed  Google Scholar 

  103. Takyar FM, Tonna S, Ho PW, Crimeen-Irwin B, Baker EK, Martin TJ, Sims NA (2013) EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone. J Bone Miner Res 28:912–925

    CAS  PubMed  Google Scholar 

  104. Arthur A, Zannettino A, Panagopoulos R, Koblar SA, Sims NA, Stylianou C, Matsuo K, Gronthos S (2011) EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation. Bone 48:533–542

    CAS  PubMed  Google Scholar 

  105. Tierney EG, McSorley K, Hastings CL, Cryan SA, O’Brien T, Murphy MJ, Barry FP, O’Brien FJ, Duffy GP (2013) High levels of ephrinB2 over-expression increases the osteogenic differentiation of human mesenchymal stem cells and promotes enhanced cell mediated mineralisation in a polyethyleneimine–ephrinB2 gene-activated matrix. J Control Release 165:173–182

    CAS  PubMed  Google Scholar 

  106. Arthur A, Panagopoulos RA, Cooper L, Menicanin D, Parkinson IH, Codrington JD, Vandyke K, Zannettino AC, Koblar SA, Sims NA, Matsuo K, Gronthos S (2013) EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair. J Bone Miner Res 28:926–935

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Natalie A. Sims.

Additional information

The authors have stated that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tonna, S., Sims, N.A. Talking among Ourselves: Paracrine Control of Bone Formation within the Osteoblast Lineage. Calcif Tissue Int 94, 35–45 (2014). https://doi.org/10.1007/s00223-013-9738-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-013-9738-2

Keywords

Navigation