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Immune and Inflammatory Pathways are Involved in Inherent Bone Marrow Ossification

  • Symposium: Allograft Research and Transplantation
  • Published:
Clinical Orthopaedics and Related Research®

Abstract

Background

Bone marrow plays a key role in bone formation and healing. Although a subset of marrow explants ossifies in vitro without excipient osteoinductive factors, some explants do not undergo ossification. The disparity of outcome suggests a significant heterogeneity in marrow tissue in terms of its capacity to undergo osteogenesis.

Questions/Purposes

We sought to identify: (1) proteins and signaling pathways associated with osteogenesis by contrasting the proteomes of ossified and poorly ossified marrow explants; and (2) temporal changes in proteome and signaling pathways of marrow ossification in the early and late phases of bone formation.

Methods

Explants of marrow were cultured. Media conditioned by ossified (n = 4) and poorly ossified (n = 4) subsets were collected and proteins unique to each group were identified by proteomic analysis. Proteomic data were processed to assess proteins specific to the early phase (Days 1–14) and late phase (Days 15–28) of the culture period. Pathways involved in bone marrow ossification were identified through bioinformatics.

Results

Twenty-eight proteins were unique to ossified samples and eight were unique to poorly ossified ones. Twelve proteins were expressed during the early phase and 15 proteins were specific to the late phase. Several identified pathways corroborated those reported for bone formation in the literature. Immune and inflammatory pathways were specific to ossified samples.

Conclusions

The marrow explant model indicates the inflammatory and immune pathways to be an integral part of the osteogenesis process.

Clinical Relevance

These results align with the clinically reported negative effects of antiinflammatory agents on fracture healing.

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References

  1. Aspenberg P. Drugs and fracture repair. Acta Orthop. 2005;76:741–748.

    Article  PubMed  Google Scholar 

  2. Baker PJ, Garneau J, Howe L, Roopenian DC. T-cell contributions to alveolar bone loss in response to oral infection with Porphyromonas gingivalis. Acta Odontol Scand. 2001;59:222–225.

    Article  PubMed  CAS  Google Scholar 

  3. Bao B-Y, Lin VC, Huang S-H, Pao J-B, Chang T-Y, Lu T-L, Lan Y-H, Chen L-M, Ting W-C, Yang W-H, Hsieh C-J, Huang S-P. Clinical significance of tumor necrosis factor receptor superfamily member 11b polymorphism in prostate cancer. Ann Surg Oncol. 2010;17:1675–1681.

    Article  PubMed  Google Scholar 

  4. Bar-Shavit Z. Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity. 2008;41:195–203.

    Article  PubMed  CAS  Google Scholar 

  5. Blanchard F, Duplomb L, Baud’huin M, Brounais B. The dual role of IL-6-type cytokines on bone remodeling and bone tumors. Cytokine Growth Factor Rev. 2009;20:19–28.

    Article  PubMed  CAS  Google Scholar 

  6. Bruder SP, Fink DJ, Caplan AI. Mesenchymal stem-cells in bone-development, bone repair, and skeletal regeneration therapy. J Cell Biochem. 1994;56:283–294.

    Article  PubMed  CAS  Google Scholar 

  7. Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000;14:6–16.

    PubMed  CAS  Google Scholar 

  8. Carlson J, Cui W, Zhang Q, Xu X, Mercan F, Bennett AM, Vignery A. Role of MKP-1 in osteoclasts and bone homeostasis. Am J Pathol. 2009;175:1564–1573.

    Article  PubMed  CAS  Google Scholar 

  9. Celebi B, Elcin AE, Elcin YM. Proteome analysis of rat bone marrow mesenchymal stem cell differentiation. J Proteome Res. 2010;9:5217–5227.

    Article  PubMed  CAS  Google Scholar 

  10. Celebi B, Elcin YM. Proteome analysis of rat bone marrow mesenchymal stem cell subcultures. J Proteome Res. 2009;8:2164–2172.

    Article  PubMed  CAS  Google Scholar 

  11. Chiellini C, Cochet O, Negroni L, Samson M, Poggi M, Ailhaud G, Alessi MC, Dani C, Amri EZ. Characterization of human mesenchymal stem cell secretome at early steps of adipocyte and osteoblast differentiation. BMC Mol. Biol. 2008;9.

  12. Cho HH, Shin KK, Kim YJ, Song JS, Kim JM, Bae YC, Kim CD, Jung JS. NF-kappaB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression. J Cell Physiol. 2010;223:168–177.

    PubMed  CAS  Google Scholar 

  13. Cho MH, Lee JH, Ahn HH, Lee JY, Kim ES, Kang YM, Min BH, Kim JH, Lee HB, Kim MS. Induction of neurogenesis in rat bone marrow mesenchymal stem cells using purine structure-based compounds. Mol Biosyst. 2009;5:609–611.

    Article  PubMed  CAS  Google Scholar 

  14. Choi YA, Lim J, Kim KM, Acharya B, Cho JY, Bae YC, Shin HI, Kim SY, Park EK. Secretome analysis of human BMSCs and identification of SMOC1 as an important ECM protein in osteoblast differentiation. J. Proteome Res. 2010;9:2946–2956.

    Article  PubMed  CAS  Google Scholar 

  15. Cooper CR, Sikes RA, Nicholson BE, Sun Y-X, Pienta KJ, Taichman RS. Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Cancer Treat Res. 2004;118:291–309.

    Article  PubMed  CAS  Google Scholar 

  16. Coxon FP, Taylor A. Vesicular trafficking in osteoclasts. Semin Cell Dev Biol. 2008;19:424–433.

    Article  PubMed  CAS  Google Scholar 

  17. Czupalla C, Mansukoski H, Riedl T, Thiel D, Krause E, Hoflack B. Proteomic analysis of lysosomal acid hydrolases secreted by osteoclasts—implications for lytic enzyme transport and bone metabolism. Mol Cell Proteomics. 2006;5:134–143.

    PubMed  CAS  Google Scholar 

  18. Dohle E, Fuchs S, Kolbe M, Hofmann A, Schmidt H, Kirkpatrick CJ. Comparative study assessing effects of sonic hedgehog and VEGF in a human co-culture model for bone vascularisation strategies. Eur Cell Mater. 2011;21:144–156.

    PubMed  CAS  Google Scholar 

  19. Fedarko NS, Fohr B, Robey PG, Young MF, Fisher LW. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. J Biol Chem. 2000;275:16666–16672.

    Article  PubMed  CAS  Google Scholar 

  20. Foster LJ, Zeemann PA, Li C, Mann M, Jensen ON, Kassem M. Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation. Stem Cells. 2005;23:1367–1377.

    Article  PubMed  CAS  Google Scholar 

  21. Fung S, Wang F, Chase M, Godt D, Hartenstein V. Expression profile of the cadherin family in the developing Drosophila brain. J Comp Neurol. 2008;506:469–488.

    Article  PubMed  CAS  Google Scholar 

  22. Galli C, Passeri G, Ravanetti F, Elezi E, Pedrazzoni M, Macaluso GM. Rough surface topography enhances the activation of Wnt/beta-catenin signaling in mesenchymal cells. J Biomed Mater Res A. 2010;95:682–690.

    PubMed  Google Scholar 

  23. Ganss B, Jheon A. Zinc finger transcription factors in skeletal development. Crit Rev Oral Biol Med. 2004;15:282–297.

    Article  PubMed  Google Scholar 

  24. Gao Y, Grassi F, Ryan MR, Terauchi M, Page K, Yang X, Weitzmann MN, Pacifici R. IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 2007;117:122–132.

    Article  PubMed  CAS  Google Scholar 

  25. Gomes I, Sharma TT, Mahmud N, Kapp JD, Edassery S, Fulton N, Liang J, Hoffman R, Westbrook CA. Highly abundant genes in the transcriptosome of human and baboon CD34 antigen-positive bone marrow cells. Blood. 2001;98:93–99.

    Article  PubMed  CAS  Google Scholar 

  26. Gu J, Zhang QH, Huang QH, Ren SX, Wu XY, Ye M, Huang CH, Fu G, Zhou J, Niu C, Han ZG, Chen SJ, Chen Z. Gene expression in CD34(+) cells from normal bone marrow and leukemic origins. Hematol J. 2000;1:206–217.

    Article  PubMed  CAS  Google Scholar 

  27. Guo DM, Tan WF, Wang F, Lv Z, Hu J, Lv TR, Chen Q, Gu XY, Wan B, Zhang ZN. Proteomic analysis of human articular cartilage: identification of differentially expressed proteins in knee osteoarthritis. Joint Bone Spine. 2008;75:439–444.

    Article  PubMed  CAS  Google Scholar 

  28. Gurkan UA, Akkus O. The mechanical environment of bone marrow: a review. Ann. Biomed. Eng. 2008;36:1978–1991.

    Article  PubMed  Google Scholar 

  29. Gurkan UA, Gargac J, Akkus O. The sequential production profiles of growth factors and their relations to bone volume in ossifying bone marrow explants. Tissue Eng Part A. 2010;16:2295–2306.

    Article  PubMed  CAS  Google Scholar 

  30. Gurkan UA, Kishore V, Condon KW, Bellido TM, Akkus O. A scaffold-free multicellular three-dimensional in vitro model of osteogenesis. Calcif Tissue Int. 2011;88:388–401.

    Article  PubMed  CAS  Google Scholar 

  31. Gurkan UA, Krueger A, Akkus O. Ossifying bone marrow explant culture as a three-dimensional mechanoresponsive in vitro model of osteogenesis. Tissue Eng Part A. 2011;17:417–428.

    Article  PubMed  CAS  Google Scholar 

  32. Ha BG, Hong JM, Park J-Y, Ha M-H, Kim T-H, Choi J-Y, Ryoo H-M, Choi J-Y, Shi, H-I, Chun SY, Kim S-Y, Park EK. Proteomic profile of osteoclast membrane proteins: identification of Na +/H + exchanger domain containing 2 and its role in osteoclast fusion. Proteomics. 2008;8:2625–2639.

    Article  PubMed  CAS  Google Scholar 

  33. Hasegawa K, Wakino S, Tanaka T, Kimoto M, Tatematsu S, Kanda T, Yoshioka K, Homma K, Sugano N, Kurabayashi M, Saruta T, Hayashi K. Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26:1488–1494.

    Article  PubMed  CAS  Google Scholar 

  34. Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFalpha promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-kappaB signaling pathway. Bone. 2009;45:367–376.

    Article  PubMed  CAS  Google Scholar 

  35. Hidalgo-Bastida LA, Cartmell SH. Mesenchymal stem cells, osteoblasts and extracellular matrix proteins: enhancing cell adhesion and differentiation for bone tissue engineering. Tissue Eng Part B Rev. 2010;16:405–412.

    Article  PubMed  CAS  Google Scholar 

  36. Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R, Long F. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14:306–314.

    Article  PubMed  CAS  Google Scholar 

  37. Hoock TC, Peters LL, Lux SE. Isoforms of ankyrin-3 that lack the NH2-terminal repeats associate with mouse macrophage lysosomes. J Cell Biol. 1997;136:1059–1070.

    Article  PubMed  CAS  Google Scholar 

  38. Huang Z, Nelson ER, Smith RL, Goodman SB. The sequential expression profiles of growth factors from osteoprogenitors [correction of osteroprogenitors] to osteoblasts in vitro. Tissue Eng. 2007;13:2311–2320.

    Article  PubMed  CAS  Google Scholar 

  39. Huber C, Martensson A, Bokoch GM, Nemazee D, Gavin AL. FGD2, a CDC42-specific exchange factor expressed by antigen-presenting cells, localizes to early endosomes and active membrane ruffles. J Biol Chem. 2008;283:34002–34012.

    Article  PubMed  CAS  Google Scholar 

  40. Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A, Gambacorti-Passerini C, Calabretta B, Perrotti D. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol. 2002;22:2255–2266.

    Article  PubMed  CAS  Google Scholar 

  41. Johnson ML, Kamel MA. The Wnt signaling pathway and bone metabolism. Curr Opin Rheumatol. 2007;19:376–382.

    Article  PubMed  CAS  Google Scholar 

  42. Jones CM, Lyons KM, Hogan BLM. Involvement of bone morphogenetic protein-4 (BMP-4) and VGR-1 in morphogenesis and neurogenesis in the mouse. Development. 1991;111:531.

    PubMed  CAS  Google Scholar 

  43. Jones KS, Bluck LJC, Wang LY, Stephen AM, Prynne CJ Coward WA. The effect of different meals on the absorption of stable isotope-labelled phylloquinone. Br J Nutr. 2009;102:1195–1202.

    Article  PubMed  CAS  Google Scholar 

  44. Kastelan D, Kastelan M, Massari LP, Korsic M. Possible association of psoriasis and reduced bone mineral density due to increased TNF-alpha and IL-6 concentrations. Med Hypotheses. 2006;67:1403–1405.

    Article  PubMed  CAS  Google Scholar 

  45. Kawai A, Kondo T, Suehara Y, Kikuta K, Hirohashi S. Global protein-expression analysis of bone and soft tissue sarcomas. Clin Orthop Relat Res. 2008;466:2099–2106.

    Article  PubMed  Google Scholar 

  46. Kelly PA, Finidori J, Moulin S, Kedzia C, Binart N. Growth hormone receptor signalling and actions in bone growth. Horm Res. 2001;55:14–17.

    Article  PubMed  CAS  Google Scholar 

  47. Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis. 2005;46:186–202.

    Article  PubMed  CAS  Google Scholar 

  48. Kiernan UA. Quantitation of target proteins and post-translational modifications in affinity-based proteomics approaches. Expert Rev Proteomics. 2007;4:421–428.

    Article  PubMed  CAS  Google Scholar 

  49. Kirkpatrick CJ, Fuchs S, Unger RE. Co-culture systems for vascularization—learning from nature. Adv Drug Deliv Rev. 2011;63:291–299.

    Article  PubMed  CAS  Google Scholar 

  50. Kubota T, Michigami T, Ozono K. Wnt signaling in bone metabolism. J Bone Miner Metab. 2009;27:265–271.

    Article  PubMed  CAS  Google Scholar 

  51. Lawe DC, Sitouah N, Hayes S, Chawla A, Virbasius JV, Tuft R, Fogarty K, Lifshitz L, Lambright D, Corvera S. Essential role of Ca2 +/calmodulin in early endosome antigen-1 localization. Mol Biol Cell. 2003;14:2935–2945.

    Article  PubMed  CAS  Google Scholar 

  52. Leiper JM, Maria JS, Chubb A, MacAllister RJ, Charles IG, Whitley GSJ, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999;343:209–214.

    Article  PubMed  CAS  Google Scholar 

  53. Lennon DP, Haynesworth SE, Young RG, Dennis JE, Caplan AI. A chemically-defined medium supports in-vitro proliferation and maintains the osteochondral potential of rat marrow-derived mesenchymal stem-cells. Exp Cell Res. 1995;219:211–222.

    Article  PubMed  CAS  Google Scholar 

  54. Li G, Dickson GR, Marsh DR, Simpson H. Rapid new bone tissue remodeling during distraction osteogenesis is associated with apoptosis. J Orthop Res. 2003;21:28–35.

    Article  PubMed  CAS  Google Scholar 

  55. Lind T, McKie N, Wendel M, Racey, SN, Birch MA. The hyalectan degrading ADAMTS-1 enzyme is expressed by osteoblasts and up-regulated at regions of new bone formation. Bone. 2005;36:408–417.

    Article  PubMed  CAS  Google Scholar 

  56. Link AJ, Eng J, Schieltz DM, Carmack E, Mize GJ, Morris DR, Garvik BM, Yates JR. Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol. 1999;17:676–682.

    Article  PubMed  CAS  Google Scholar 

  57. Luria EA, Owen M, Friedenstein AJ, Morris J, Kuznetsow SA, Joyner C. Bone formation in organ culture of marrow pieces. Cell Tissue Res. 1986;7:313.

    Google Scholar 

  58. Machold RP, Kittell DJ, Fishell GJ. Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Dev. 2007;2:5.

    Article  PubMed  CAS  Google Scholar 

  59. Macias MP, Fitzpatrick LA, Brenneise I, McGarry MP, Lee JJ, Lee NA. Expression of IL-5 alters bone metabolism and induces ossification of the spleen in transgenic mice. J Clin Invest. 2001;107:949–959.

    Article  PubMed  CAS  Google Scholar 

  60. Mann M, Jensen ON. Proteomic analysis of post-translational modifications. Nat Biotechnol. 2003;21:255–261.

    Article  PubMed  CAS  Google Scholar 

  61. Mareddy S, Broadbent J, Crawford R, Xiao Y. Proteomic profiling of distinct clonal populations of bone marrow mesenchymal stem cells. J Cell Biochem. 2009;106:776–786.

    Article  PubMed  CAS  Google Scholar 

  62. Miyanishi K, Yamamoto T, Irisa T, Noguchi Y, Sugioka Y, Iwamoto Y. Increased level of apolipoprotein B/apolipoprotein A1 ratio as a potential risk for osteonecrosis. Ann Rheum Dis. 1999;58:514–516.

    Article  PubMed  CAS  Google Scholar 

  63. Morgan EF, Mason ZD, Chien KB, Pfeiffer AJ, Barnes GL, Einhorn TA, Gerstenfeld LC. Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function. Bone. 2009;44:335–344.

    Article  PubMed  Google Scholar 

  64. Mukae H, Hogg JC, English D, Vincent R, Van Eeden SF. Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow. Am J Physiol Lung Cell Mol Physiol. 2000;279:L924–L931.

    PubMed  CAS  Google Scholar 

  65. Mukherjee A, Rotwein P. Akt promotes BMP2-mediated osteoblast differentiation and bone development. J Cell Sci. 2009;122:716–726.

    Article  PubMed  CAS  Google Scholar 

  66. Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E, Prosperini E, Vigo E, Oliner JD, Helin K. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 2001;15:267–285.

    Article  PubMed  CAS  Google Scholar 

  67. Muller R, Van Campenhout H, Van Damme B, Van Der Perre G, Dequeker J, Hildebrand T, Ruegsegger P. Morphometric analysis of human bone biopsies: a quantitative structural comparison of histological sections and micro-computed tomography. Bone. 1998;23:59–66.

    Article  PubMed  CAS  Google Scholar 

  68. Nagayama M, Iwamoto M, Hargett A, Kamiya N, Tamamura Y, Young B, Morrison T, Takeuchi H, Pacifici M, Enomoto-Iwamoto M, Koyama E. Wnt/beta-catenin signaling regulates cranial base development and growth. J Dent Res. 2008;87:244–249.

    Article  PubMed  CAS  Google Scholar 

  69. Nakanishi H, Takai Y. Frabin and other related Cdc42-specific guanine nucleotide exchange factors couple the actin cytoskeleton with the plasma membrane. J Cell Mol Med. 2008;12:1169–1176.

    Article  PubMed  CAS  Google Scholar 

  70. Naot D, Grey A, Reid IR, Cornish J. Lactoferrin—a novel bone growth factor. Clin Med Res. 2005;3:93–101.

    Article  PubMed  Google Scholar 

  71. Neale SD, Haynes DR, Howie DW, Murray DW, Athanasou NA. The effect of particle phagocytosis and metallic wear particles on osteoclast formation and bone resorption in vitro. J Arthroplasty. 2000;15:654–662.

    Article  PubMed  CAS  Google Scholar 

  72. Nemoto T, Kajiya H, Tsuzuki T, Takahashi Y, Okabe K. Differential induction of collagens by mechanical stress in human periodontal ligament cells. Arch Oral Biol. 2010;55:981–987.

    Article  PubMed  CAS  Google Scholar 

  73. Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res. 2007;25:941–950.

    Article  PubMed  CAS  Google Scholar 

  74. Oh I-H. Microenvironmental targeting of Wnt/beta-catenin signals for hematopoietic stem cell regulation. Expert Opin Biol Ther. 2010;10:1315–1329.

    Article  PubMed  CAS  Google Scholar 

  75. Okabe T, Ohmori Y, Tanigami A, Hishigaki H, Suzuki Y, Sugano S, Kawaguchi A, Nakaya H, Wakitani S. Detection of gene expression in synovium of patients with osteoarthritis using a random sequencing method. Acta Orthop. 2007;78:687–692.

    Article  PubMed  Google Scholar 

  76. Oldershaw RA, Hardingham TE. Notch signaling during chondrogenesis of human bone marrow stem cells. Bone. 2010;46:286–293.

    Article  PubMed  CAS  Google Scholar 

  77. Oldershaw RA, Tew SR, Russell AM, Meade K, Hawkins R, McKay TR, Brennan KR, Hardingham TE. Notch signaling through jagged-1 is necessary to initiate chondrogenesis in human bone marrow stromal cells but must be switched off to complete chondrogenesis. Stem Cells. 2008;26:666–674.

    Article  PubMed  CAS  Google Scholar 

  78. Oyama M, Kozuka-Hata H, Suzuki Y, Semba K, Yamamoto T, Sugano S. Diversity of translation start sites may define increased complexity of the human short ORFeome. Mol Cell Proteomics. 2007;6:1000–1006.

    Article  PubMed  CAS  Google Scholar 

  79. Palumbo C, Ferretti M, De Pol A. Apoptosis during intramernbranous ossification. J Anat. 2003;203:589–598.

    Article  PubMed  Google Scholar 

  80. Papadimitropoulos A, Scherberich A, Guven S, Theilgaard N, Crooijmans HJ, Santini F, Scheffler K, Zallone A, Martin I. A 3D in vitro bone organ model using human progenitor cells. Eur Cell Mater. 2011;21:445–458; discussion 458.

    PubMed  CAS  Google Scholar 

  81. Pfister O, Oikonomopoulos A, Sereti K-I, Sohn RL, Cullen D, Fine GC, Mouquet F, Westerman K, Liao R. Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res. 2008;103:825-U110.

    Google Scholar 

  82. Pufe T, Wildemann B, Petersen W, Mentlein R, Raschke M, Schmidmaier G. Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat. Cell Tissue Res. 2002;309:387–392.

    Article  PubMed  CAS  Google Scholar 

  83. Rabinovitch M, Destefano MJ. In vitro chemotaxis of mouse bone marrow neutrophils. Proc Soc Exp Biol Med. 1978;158:170–173.

    PubMed  CAS  Google Scholar 

  84. Schmutz S, Fuchs T, Regenfelder F, Steinmann P, Zumstein M, Fuchs B. Expression of atrophy mRNA relates to tendon tear size in supraspinatus muscle. Clin Orthop Relat Res. 2009;467:457–464.

    Article  PubMed  Google Scholar 

  85. Silkstone D, Hong H, Alman BA. beta-Catenin in the race to fracture repair: in it to Wnt. Nat Clin Pract Rheumatol. 2008;4:413–419.

    Article  PubMed  CAS  Google Scholar 

  86. Sioud M, Floisand Y. TLR agonists induce the differentiation of human bone marrow CD34(+) progenitors into CD11c(+) CD80/86(+) DC capable of inducing a Th1-type response. Eur J Immunol. 2007;37:2834–2846.

    Article  PubMed  CAS  Google Scholar 

  87. Spreafico A, Frediani B, Capperucci C, Chellini F, Paffetti A, D’Ambrosio C, Bernardini G, Mini R, Collodel G, Scaloni A, Marcolongo R, Santucci A. A proteomic study on human osteoblastic cells proliferation and differentiation. Proteomics. 2006;6:3520–3532.

    Article  PubMed  CAS  Google Scholar 

  88. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Snorradottir S, Center JR, Nguyen TV, Alexandersen P, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K. New sequence variants associated with bone mineral density. Nat Genet. 2009;41:15–17.

    Article  PubMed  CAS  Google Scholar 

  89. Takahashi-Yanaga F, Sasaguri T. The Wnt/beta-catenin signaling pathway as a target in drug discovery. J Pharmacol Sci. 2007;104:293–302.

    Article  PubMed  CAS  Google Scholar 

  90. Tan XY, Cai DZ, Wu YL, Liu B, Rong LM, Chen ZS, Zhao QC. Comparative analysis of serum proteomes: discovery of proteins associated with osteonecrosis of the femoral head. Transl Res. 2006;148:114–119.

    Article  PubMed  CAS  Google Scholar 

  91. Towers M, Fisunov G, Tickle C. Expression of E2F transcription factor family genes during chick wing development. Gene Expr Patterns. 2009;9:528–531.

    Article  PubMed  CAS  Google Scholar 

  92. Toyosaki-Maeda T, Takano H, Tomita T, Tsuruta Y, Maeda-Tanimura M, Shimaoka Y, Takahashi T, Itoh T, Suzuki R, Ochi T. Differentiation of monocytes into multinucleated giant bone-resorbing cells: two-step differentiation induced by nurse-like cells and cytokines. Arthritis Res. 2001;3:306–310.

    Article  PubMed  CAS  Google Scholar 

  93. Tsangari H, Findlay DM, Kuliwaba JS, Atkins GJ, Fazzalari NL. Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of the femoral neck. Bone. 2004;35:334–342.

    Article  PubMed  CAS  Google Scholar 

  94. Tsangari H, Findlay DM, Zannettino ACW, Pan B, Kuliwaba JS, Fazzalari NL. Evidence for reduced bone formation surface relative to bone resorption surface in female femoral fragility fracture patients. Bone. 2006;39:1226–1235.

    Article  PubMed  Google Scholar 

  95. Ugarte F, Ryser M, Thieme S, Fierro FA, Navratiel K, Bornhaeuser M, Brenner S. Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp Hematol. 2009;37:867–875.

    Article  PubMed  CAS  Google Scholar 

  96. Vaaraniemi J, Halleen JM, Kaarlonen K, Ylipahkala H, Alatalo SL, Andersson G, Kaija H, Vihko P, Vaananen HK. Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res. 2004;19:1432–1440.

    Article  PubMed  CAS  Google Scholar 

  97. Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008;102:10–14.

    PubMed  CAS  Google Scholar 

  98. Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J, Choi Y. Osteoimmunology: interplay between the immune system and bone metabolism. Ann Rev Immunol. 2006;24:33–63.

    Article  CAS  Google Scholar 

  99. Wan C, He Q, McCaigue M, Marsh D, Li G. Nonadherent cell population of human marrow culture is a complementary source of mesenchymal stem cells (MSCs). J Orthop Res. 2006;24:21–28.

    Article  PubMed  Google Scholar 

  100. Wang W, Ferguson DJP, Quinn JMW, Simpson A, Athanasou NA. Osteoclasts are capable of particle phagocytosis and bone resorption. J Pathol. 1997;182:92–98.

    Article  PubMed  CAS  Google Scholar 

  101. Weber JM, Calvi LM. Notch signaling and the bone marrow hematopoietic stem cell niche. Bone. 2010;46:281–285.

    Article  PubMed  CAS  Google Scholar 

  102. Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.

    Article  PubMed  CAS  Google Scholar 

  103. Zhang AX, Yu WH, Ma BF, Yu XB, Mao FF, Liu W, Zhang, JQ, Zhang XM, Li SN, Li MT, Lahn BT, Xiang AP. Proteomic identification of differently expressed proteins responsible for osteoblast differentiation from human mesenchymal stem cells. Mol Cell Biochem. 2007;304:167–179.

    Article  PubMed  CAS  Google Scholar 

  104. Zhang HW, Recker R, Lee WNP, Xiao GGS. Proteomics in bone research. Expert Rev Proteomics. 2010;7:103–111.

    Article  PubMed  Google Scholar 

  105. Zhao HB, Ettala O, Vaananen HK. Intracellular membrane trafficking pathways in bone-resorbing osteoclasts revealed by cloning and subcellular localization studies of small GTP-binding rab proteins. Biochem Biophys Res Commun. 2002;293:1060–1065.

    Article  PubMed  CAS  Google Scholar 

  106. Zhu H, Miosge N, Schulz J, Schliephake H. Regulation of multilineage gene expression and apoptosis during in vitro expansion of human bone marrow stromal cells with different cell culture media. Cells Tissues Organs. 2010;192:211–220.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank David VanSickle PhD, DVM for insightful discussions on bone marrow ossification model and Pamela Lachik for help with the μCT system.

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Authors and Affiliations

  1. Harvard-MIT Division of Health Sciences and Technology, Brigham and Women’s Hospital, Harvard Medical School, 65 Landsdowne Street, PRB 252, Cambridge, MA, 02139, USA

    Umut Atakan Gurkan PhD

  2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

    Ryan Golden BS

  3. Department of Mechanical and Aerospace Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Vipuil Kishore PhD & Ozan Akkus PhD

  4. Department of Research and Development Pathology Associates, Medical Laboratories, Spokane, WA, 99204, USA

    Catherine P. Riley MS

  5. Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA

    Jiri Adamec PhD

  6. Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Ozan Akkus PhD

  7. Department of Orthopaedics, University Hospitals of Cleveland, Cleveland, OH, USA

    Ozan Akkus PhD

Authors
  1. Umut Atakan Gurkan PhD
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  2. Ryan Golden BS
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  3. Vipuil Kishore PhD
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  4. Catherine P. Riley MS
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  5. Jiri Adamec PhD
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  6. Ozan Akkus PhD
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Corresponding authors

Correspondence to Umut Atakan Gurkan PhD or Ozan Akkus PhD.

Additional information

This study was funded by a grant from the Musculoskeletal Transplant Foundation (OA).

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

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Gurkan, U.A., Golden, R., Kishore, V. et al. Immune and Inflammatory Pathways are Involved in Inherent Bone Marrow Ossification. Clin Orthop Relat Res 470, 2528–2540 (2012). https://doi.org/10.1007/s11999-012-2459-4

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  • DOI: https://doi.org/10.1007/s11999-012-2459-4

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