Advertisement

Determinants of stem cell lineage differentiation toward chondrogenesis versus adipogenesis

  • Sheng Zhou
  • Song Chen
  • Qing Jiang
  • Ming PeiEmail author
Review
First Online:
  • 123 Downloads

Abstract

Adult stem cells, also termed as somatic stem cells, are undifferentiated cells, detected among differentiated cells in a tissue or an organ. Adult stem cells can differentiate toward lineage specific cell types of the tissue or organ in which they reside. They also have the ability to differentiate into mature cells of mesenchymal tissues, such as cartilage, fat and bone. Despite the fact that the balance has been comprehensively scrutinized between adipogenesis and osteogenesis and between chondrogenesis and osteogenesis, few reviews discuss the relationship between chondrogenesis and adipogenesis. In this review, the developmental and transcriptional crosstalk of chondrogenic and adipogenic lineages are briefly explored, followed by elucidation of signaling pathways and external factors guiding lineage determination between chondrogenic and adipogenic differentiation. An in-depth understanding of overlap and discrepancy between these two mesenchymal tissues in lineage differentiation would benefit regeneration of high-quality cartilage tissues and adipose tissues for clinical applications.

Keywords

Stem cell Chondrogenesis Adipogenesis, Lineage differentiation 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

We thank Suzanne Danley for editing the manuscript. This work was supported by Research Grants from the Musculoskeletal Transplant Foundation (MTF) and the National Institutes of Health (1R01AR067747-01A1) to M.P., and Natural Science Foundation of China (81601889) to S.C.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41–49.  https://doi.org/10.1038/nature00870 CrossRefPubMedGoogle Scholar
  3. 3.
    Wagers AJ, Weissman IL (2004) Plast Adult Stem Cells. Cell 116(5):639–648CrossRefPubMedGoogle Scholar
  4. 4.
    Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q, Cao J, Xie N, Velletri T, Zhang X, Xu C, Zhang L, Yang H, Hou J, Wang Y, Shi Y (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ 23(7):1128–1139.  https://doi.org/10.1038/cdd.2015.168 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Augello A, De Bari C (2010) The regulation of differentiation in mesenchymal stem cells. Hum Gene Ther 21(10):1226–1238.  https://doi.org/10.1089/hum.2010.173 CrossRefPubMedGoogle Scholar
  6. 6.
    Chijimatsu R, Kobayashi M, Ebina K, Iwahashi T, Okuno Y, Hirao M, Fukuhara A, Nakamura N, Yoshikawa H (2018) Impact of dexamethasone concentration on cartilage tissue formation from human synovial derived stem cells in vitro. Cytotechnology 70(2):819–829.  https://doi.org/10.1007/s10616-018-0191-y CrossRefPubMedGoogle Scholar
  7. 7.
    Kirton JP, Crofts NJ, George SJ, Brennan K, Canfield AE (2007) Wnt/beta-catenin signaling stimulates chondrogenic and inhibits adipogenic differentiation of pericytes: potential relevance to vascular disease? Circ Res 101(6):581–589.  https://doi.org/10.1161/CIRCRESAHA.107.156372 CrossRefPubMedGoogle Scholar
  8. 8.
    Enomoto H, Furuichi T, Zanma A, Yamana K, Yoshida C, Sumitani S, Yamamoto H, Enomoto-Iwamoto M, Iwamoto M, Komori T (2004) Runx2 deficiency in chondrocytes causes adipogenic changes in vitro. J Cell Sci 117(Pt 3):417–425.  https://doi.org/10.1242/jcs.00866 CrossRefPubMedGoogle Scholar
  9. 9.
    Qu P, Wang L, Min Y, McKennett L, Keller JR, Lin PC (2016) Vav1 regulates mesenchymal stem cell differentiation decision between adipocyte and chondrocyte via sirt1. Stem Cells 34(7):1934–1946.  https://doi.org/10.1002/stem.2365 CrossRefPubMedGoogle Scholar
  10. 10.
    Wang Y, Sul HS (2009) Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell Metab 9(3):287–302.  https://doi.org/10.1016/j.cmet.2009.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Okazaki K, Li J, Yu H, Fukui N, Sandell LJ (2002) CCAAT/enhancer-binding proteins beta and delta mediate the repression of gene transcription of cartilage-derived retinoic acid-sensitive protein induced by interleukin-1 beta. J Biol Chem 277(35):31526–31533.  https://doi.org/10.1074/jbc.M202815200 CrossRefPubMedGoogle Scholar
  12. 12.
    Okuma T, Hirata M, Yano F, Mori D, Kawaguchi H, Chung UI, Tanaka S, Saito T (2015) Regulation of mouse chondrocyte differentiation by CCAAT/enhancer-binding proteins. Biomed Res 36(1):21–29.  https://doi.org/10.2220/biomedres.36.21 CrossRefPubMedGoogle Scholar
  13. 13.
    Ushijima T, Okazaki K, Tsushima H, Iwamoto Y (2014) CCAAT/enhancer-binding protein beta regulates the repression of type II collagen expression during the differentiation from proliferative to hypertrophic chondrocytes. J Biol Chem 289(5):2852–2863.  https://doi.org/10.1074/jbc.M113.492843 CrossRefPubMedGoogle Scholar
  14. 14.
    Stockl S, Bauer RJ, Bosserhoff AK, Gottl C, Grifka J, Grassel S (2013) Sox9 modulates cell survival and adipogenic differentiation of multipotent adult rat mesenchymal stem cells. J Cell Sci 126(Pt 13):2890–2902.  https://doi.org/10.1242/jcs.124305 CrossRefPubMedGoogle Scholar
  15. 15.
    Ushita M, Saito T, Ikeda T, Yano F, Higashikawa A, Ogata N, Chung U, Nakamura K, Kawaguchi H (2009) Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells. Osteoarthr Cartil 17(8):1065–1075.  https://doi.org/10.1016/j.joca.2009.02.003 CrossRefPubMedGoogle Scholar
  16. 16.
    Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Nakamura K, Kawaguchi H, Ikegawa S, Chung UI (2004) The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis Rheum 50(11):3561–3573.  https://doi.org/10.1002/art.20611 CrossRefPubMedGoogle Scholar
  17. 17.
    Chen S, Fu P, Wu H, Pei M (2017) Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy, development and function. Cell Tissue Res 5:6.  https://doi.org/10.1007/s00441-017-2613-0 CrossRefGoogle Scholar
  18. 18.
    Bhattacharjee M, Coburn J, Centola M, Murab S, Barbero A, Kaplan DL, Martin I, Ghosh S (2015) Tissue engineering strategies to study cartilage development, degeneration and regeneration. Adv Drug Deliv Rev 84:107–122.  https://doi.org/10.1016/j.addr.2014.08.010 CrossRefPubMedGoogle Scholar
  19. 19.
    Mikic B, Johnson TL, Chhabra AB, Schalet BJ, Wong M, Hunziker EB (2000) Differential effects of embryonic immobilization on the development of fibrocartilaginous skeletal elements. J Rehabil Res Dev 37(2):127–133PubMedGoogle Scholar
  20. 20.
    Storm EE, Kingsley DM (1996) Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. Development 122(12):3969–3979PubMedGoogle Scholar
  21. 21.
    Decker RS (2017) Articular cartilage and joint development from embryogenesis to adulthood. Semin Cell Dev Biol 62:50–56.  https://doi.org/10.1016/j.semcdb.2016.10.005 CrossRefPubMedGoogle Scholar
  22. 22.
    Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6(1):38–54.  https://doi.org/10.1016/j.cmet.2007.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454(7207):961–967.  https://doi.org/10.1038/nature07182 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sanchez-Gurmaches J, Hung CM, Sparks CA, Tang Y, Li H, Guertin DA (2012) PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab 16(3):348–362.  https://doi.org/10.1016/j.cmet.2012.08.003 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Billon N, Iannarelli P, Monteiro MC, Glavieux-Pardanaud C, Richardson WD, Kessaris N, Dani C, Dupin E (2007) The generation of adipocytes by the neural crest. Development 134(12):2283–2292.  https://doi.org/10.1242/dev.002642 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131(2):242–256.  https://doi.org/10.1016/j.cell.2007.10.004 CrossRefPubMedGoogle Scholar
  27. 27.
    Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7(12):885–896.  https://doi.org/10.1038/nrm2066 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ (2001) C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl Acad Sci USA 98(22):12532–12537.  https://doi.org/10.1073/pnas.211416898 CrossRefPubMedGoogle Scholar
  29. 29.
    Schulz TJ, Tseng YH (2009) Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 20(5–6):523–531.  https://doi.org/10.1016/j.cytogfr.2009.10.019 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Iwasaki M, Nakata K, Nakahara H, Nakase T, Kimura T, Kimata K, Caplan AI, Ono K (1993) Transforming growth factor-beta 1 stimulates chondrogenesis and inhibits osteogenesis in high density culture of periosteum-derived cells. Endocrinology 132(4):1603–1608.  https://doi.org/10.1210/endo.132.4.8462458 CrossRefPubMedGoogle Scholar
  31. 31.
    Erickson GR, Gimble JM, Franklin DM, Rice HE, Awad H, Guilak F (2002) Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. Biochem Biophys Res Commun 290(2):763–769.  https://doi.org/10.1006/bbrc.2001.6270 CrossRefPubMedGoogle Scholar
  32. 32.
    Barry F, Boynton RE, Liu B, Murphy JM (2001) Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. Exp Cell Res 268(2):189–200.  https://doi.org/10.1006/excr.2001.5278 CrossRefPubMedGoogle Scholar
  33. 33.
    Awad HA, Halvorsen YD, Gimble JM, Guilak F (2003) Effects of transforming growth factor beta1 and dexamethasone on the growth and chondrogenic differentiation of adipose-derived stromal cells. Tissue Eng 9(6):1301–1312.  https://doi.org/10.1089/10763270360728215 CrossRefPubMedGoogle Scholar
  34. 34.
    Handorf AM, Chamberlain CS, Li WJ (2015) Endogenously produced Indian Hedgehog regulates TGFbeta-driven chondrogenesis of human bone marrow stromal/stem cells. Stem Cells Dev 24(8):995–1007.  https://doi.org/10.1089/scd.2014.0266 CrossRefPubMedGoogle Scholar
  35. 35.
    Yoo JU, Barthel TS, Nishimura K, Solchaga L, Caplan AI, Goldberg VM, Johnstone B (1998) The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J Bone Joint Surg Am 80(12):1745–1757CrossRefPubMedGoogle Scholar
  36. 36.
    Kitamura H (2004) Establishment of a bipotent cell line CL-1 which differentiates into chondrocytes and adipocytes from adult mouse. Osteoarthr Cartil 12(1):25–37CrossRefPubMedGoogle Scholar
  37. 37.
    Zhou S, Eid K, Glowacki J (2004) Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res 19(3):463–470.  https://doi.org/10.1359/JBMR.0301239 CrossRefPubMedGoogle Scholar
  38. 38.
    Ignotz RA, Massague J (1985) Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci USA 82(24):8530–8534CrossRefPubMedGoogle Scholar
  39. 39.
    Tsurutani Y, Fujimoto M, Takemoto M, Irisuna H, Koshizaka M, Onishi S, Ishikawa T, Mezawa M, He P, Honjo S, Maezawa Y, Saito Y, Yokote K (2011) The roles of transforming growth factor-beta and Smad3 signaling in adipocyte differentiation and obesity. Biochem Biophys Res Commun 407(1):68–73.  https://doi.org/10.1016/j.bbrc.2011.02.106 CrossRefPubMedGoogle Scholar
  40. 40.
    Coricor G, Serra R (2016) TGF-beta regulates phosphorylation and stabilization of Sox9 protein in chondrocytes through p38 and Smad dependent mechanisms. Sci Rep 6:38616.  https://doi.org/10.1038/srep38616 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tuli R, Seghatoleslami MR, Tuli S, Howard MS, Danielson KG, Tuan RS (2002) p38 MAP kinase regulation of AP-2 binding in TGF-beta1-stimulated chondrogenesis of human trabecular bone-derived cells. Ann N Y Acad Sci 961:172–177CrossRefPubMedGoogle Scholar
  42. 42.
    Kim BS, Kang KS, Kang SK (2010) Soluble factors from ASCs effectively direct control of chondrogenic fate. Cell Prolif 43(3):249–261.  https://doi.org/10.1111/j.1365-2184.2010.00680.x CrossRefPubMedGoogle Scholar
  43. 43.
    Li J, Zhao Z, Liu J, Huang N, Long D, Wang J, Li X, Liu Y (2010) MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-beta1/Smads pathway. Cell Prolif 43(4):333–343.  https://doi.org/10.1111/j.1365-2184.2010.00682.x CrossRefPubMedGoogle Scholar
  44. 44.
    Choy L, Skillington J, Derynck R (2000) Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. J Cell Biol 149(3):667–682CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Choy L, Derynck R (2003) Transforming growth factor-beta inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J Biol Chem 278(11):9609–9619.  https://doi.org/10.1074/jbc.M212259200 CrossRefPubMedGoogle Scholar
  46. 46.
    Sekiya I, Larson BL, Vuoristo JT, Reger RL, Prockop DJ (2005) Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma. Cell Tissue Res 320(2):269–276.  https://doi.org/10.1007/s00441-004-1075-3 CrossRefPubMedGoogle Scholar
  47. 47.
    Sottile V, Seuwen K (2000) Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone). FEBS Lett 475(3):201–204CrossRefPubMedGoogle Scholar
  48. 48.
    Wang EA, Israel DI, Kelly S, Luxenberg DP (1993) Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors 9(1):57–71CrossRefPubMedGoogle Scholar
  49. 49.
    Schmitt B, Ringe J, Haupl T, Notter M, Manz R, Burmester GR, Sittinger M, Kaps C (2003) BMP2 initiates chondrogenic lineage development of adult human mesenchymal stem cells in high-density culture. Res Biol Divers 71(9–10):567–577.  https://doi.org/10.1111/j.1432-0436.2003.07109003.x CrossRefGoogle Scholar
  50. 50.
    Kuroda R, Usas A, Kubo S, Corsi K, Peng HR, Rose T, Cummins J, Fu FH, Huard J (2006) Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Arthritis Rheum 54(2):433–442.  https://doi.org/10.1002/art.21632 CrossRefPubMedGoogle Scholar
  51. 51.
    Steinert A, Weber M, Dimmler A, Julius C, Schutze N, Noth U, Cramer H, Eulert J, Zimmermann U, Hendrich C (2003) Chondrogenic differentiation of mesenchymal progenitor cells encapsulated in ultrahigh-viscosity alginate. J Orthopaed Res 21(6):1090–1097.  https://doi.org/10.1016/S0736-0266(03)00100-1 CrossRefGoogle Scholar
  52. 52.
    Semba I, Nonaka K, Takahashi I, Takahashi K, Dashner R, Shum L, Nuckolls GH, Slavkin HC (2000) Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Dev Dynam 217(4):401–414.  https://doi.org/10.1002/(Sici)1097-0177(200004)217:4%3c401:Aid-Dvdy7%3e3.0.Co;2-D CrossRefGoogle Scholar
  53. 53.
    Nakayama N, Duryea D, Manoukian R, Chow G, Han CYE (2003) Macroscopic cartilage formation with embryonic stem-cell-derived mesodermal progenitor cells. J Cell Sci 116(10):2015–2028.  https://doi.org/10.1242/jcs.00417 CrossRefPubMedGoogle Scholar
  54. 54.
    Taha MF, Valojerdi MR, Mowla SJ (2006) Effect of bone morphogenetic protein-4 (BMP-4) on adipocyte differentiation from mouse embryonic stem cells. Anat Histol Embryol 35(4):271–278.  https://doi.org/10.1111/j.1439-0264.2006.00680.x CrossRefPubMedGoogle Scholar
  55. 55.
    Shintani N, Hunziker EB (2007) Chondrogenic differentiation of bovine synovium—bone morphogenetic proteins 2 and 7 and transforming growth factor beta 1 induce the formation of different types of cartilaginous tissue. Arthritis Rheum 56(6):1869–1879.  https://doi.org/10.1002/art.22701 CrossRefPubMedGoogle Scholar
  56. 56.
    Miyamoto C, Matsumoto T, Sakimura K, Shindo H (2007) Osteogenic protein-1 with transforming growth factor-beta 1: potent inducer of chondrogenesis of synovial mesenchymal stem cells in vitro. J Orthop Sci 12(6):555–561.  https://doi.org/10.1007/s00776-007-1176-4 CrossRefPubMedGoogle Scholar
  57. 57.
    Brown PT, Squire MW, Li WJ (2014) Characterization and evaluation of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Cell Tissue Res 358(1):149–164.  https://doi.org/10.1007/s00441-014-1926-5 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Cicione C, Muinos-Lopez E, Hermida-Gomez T, Fuentes-Boquete I, Diaz-Prado S, Blanco FJ (2015) Alternative protocols to induce chondrogenic differentiation: transforming growth factor-beta superfamily. Cell Tissue Bank 16(2):195–207.  https://doi.org/10.1007/s10561-014-9472-7 CrossRefPubMedGoogle Scholar
  59. 59.
    Lee PT, Li WJ (2017) Chondrogenesis of embryonic stem cell-derived mesenchymal stem cells induced by TGF1 and BMP7 through increased TGF receptor expression and endogenous TGF1 production. J Cell Biochem 118(1):172–181.  https://doi.org/10.1002/jcb.25623 CrossRefPubMedGoogle Scholar
  60. 60.
    Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454(7207):1000–1044.  https://doi.org/10.1038/nature07221 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Neumann K, Endres M, Ringe J, Flath B, Manz R, Haupl T, Sittinger M, Kaps C (2007) BMP7 promotes adipogenic but not osteo-/chondrogenic differentiation of adult human bone marrow-derived stem cells in high-density micro-mass culture. J Cell Biochem 102(3):626–637.  https://doi.org/10.1002/jcb.21319 CrossRefPubMedGoogle Scholar
  62. 62.
    Shen B, Wei A, Whittaker S, Williams LA, Tao H, Ma DD, Diwan AD (2010) The role of BMP-7 in chondrogenic and osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells in vitro. J Cell Biochem 109(2):406–416.  https://doi.org/10.1002/jcb.22412 CrossRefPubMedGoogle Scholar
  63. 63.
    Spinella-Jaegle S, Rawadi G, Kawai S, Gallea S, Faucheu C, Mollat P, Courtois B, Bergaud B, Ramez V, Blanchet AM, Adelmant G, Baron R, Roman-Roman S (2001) Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci 114(Pt 11):2085–2094PubMedGoogle Scholar
  64. 64.
    Fontaine C, Cousin W, Plaisant M, Dani C, Peraldi P (2008) Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells 26(4):1037–1046.  https://doi.org/10.1634/stemcells.2007-0974 CrossRefPubMedGoogle Scholar
  65. 65.
    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(5275):663–666CrossRefPubMedGoogle Scholar
  66. 66.
    St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13(16):2072–2086CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Mundy C, Bello A, Sgariglia F, Koyama E, Pacifici M (2016) HhAntag, a hedgehog signaling antagonist, suppresses chondrogenesis and modulates canonical and non-canonical BMP signaling. J Cell Physiol 231(5):1033–1044.  https://doi.org/10.1002/jcp.25192 CrossRefPubMedGoogle Scholar
  68. 68.
    Enomoto-Iwamoto M, Nakamura T, Aikawa T, Higuchi Y, Yuasa T, Yamaguchi A, Nohno T, Noji S, Matsuya T, Kurisu K, Koyama E, Pacifici M, Iwamoto M (2000) Hedgehog proteins stimulate chondrogenic cell differentiation and cartilage formation. J Bone Miner Res 15(9):1659–1668.  https://doi.org/10.1359/jbmr.2000.15.9.1659 CrossRefPubMedGoogle Scholar
  69. 69.
    James AW, Leucht P, Levi B, Carre AL, Xu Y, Helms JA, Longaker MT (2010) Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A 16(8):2605–2616.  https://doi.org/10.1089/ten.TEA.2010.0048 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Suh JM, Gao X, McKay J, McKay R, Salo Z, Graff JM (2006) Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab 3(1):25–34.  https://doi.org/10.1016/j.cmet.2005.11.012 CrossRefPubMedGoogle Scholar
  71. 71.
    Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM (2010) Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell 140(1):148–160.  https://doi.org/10.1016/j.cell.2009.12.027 CrossRefPubMedGoogle Scholar
  72. 72.
    Zehentner BK, Leser U, Burtscher H (2000) BMP-2 and sonic hedgehog have contrary effects on adipocyte-like differentiation of C3H10T1/2 cells. DNA Cell Biol 19(5):275–281.  https://doi.org/10.1089/10445490050021186 CrossRefPubMedGoogle Scholar
  73. 73.
    Kim W, Kim M, Jho EH (2013) Wnt/beta-catenin signalling: from plasma membrane to nucleus. Biochem J 450:9–21CrossRefPubMedGoogle Scholar
  74. 74.
    Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779.  https://doi.org/10.1038/nrm3470 CrossRefPubMedGoogle Scholar
  75. 75.
    Fischer L, Boland G, Tuan RS (2002) Wnt-3A enhances bone morphogenetic protein-2-mediated chondrogenesis of murine C3H10T1/2 mesenchymal cells. J Biol Chem 277(34):30870–30878.  https://doi.org/10.1074/jbc.M109330200 CrossRefPubMedGoogle Scholar
  76. 76.
    Im GI, Quan Z (2010) The effects of Wnt inhibitors on the chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 16(7):2405–2413.  https://doi.org/10.1089/ten.TEA.2009.0359 CrossRefPubMedGoogle Scholar
  77. 77.
    Laudes M (2011) Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes. J Mol Endocrinol 46(2):R65–R72.  https://doi.org/10.1530/JME-10-0169 CrossRefPubMedGoogle Scholar
  78. 78.
    Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289(5481):950–953CrossRefPubMedGoogle Scholar
  79. 79.
    Liu J, Farmer SR (2004) Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem 279(43):45020–45027.  https://doi.org/10.1074/jbc.m407050200 CrossRefPubMedGoogle Scholar
  80. 80.
    Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR (2003) Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J 376(Pt 3):607–613.  https://doi.org/10.1042/BJ20030426 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibanez G, MacDougald OA (2012) Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism. Bone 50(2):477–489.  https://doi.org/10.1016/j.bone.2011.08.010 CrossRefPubMedGoogle Scholar
  82. 82.
    Kawai M, Mushiake S, Bessho K, Murakami M, Namba N, Kokubu C, Michigami T, Ozono K (2007) Wnt/Lrp/beta-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARgamma and C/EBPalpha. Biochem Biophys Res Commun 363(2):276–282.  https://doi.org/10.1016/j.bbrc.2007.08.088 CrossRefPubMedGoogle Scholar
  83. 83.
    Park JR, Jung JW, Lee YS, Kang KS (2008) The roles of Wnt antagonists Dkk1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells. Cell Prolif 41(6):859–874.  https://doi.org/10.1111/j.1365-2184.2008.00565.x CrossRefPubMedGoogle Scholar
  84. 84.
    Ehrlund A, Mejhert N, Lorente-Cebrian S, Astrom G, Dahlman I, Laurencikiene J, Ryden M (2013) Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue. J Clin Endocrinol Metab 98(3):E503–E508.  https://doi.org/10.1210/jc.2012-3416 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277(34):30998–31004.  https://doi.org/10.1074/jbc.M204527200 CrossRefPubMedGoogle Scholar
  86. 86.
    Fairfield H, Falank C, Harris E, Demambro V, McDonald M, Pettitt JA, Mohanty ST, Croucher P, Kramer I, Kneissel M, Rosen CJ, Reagan MR (2018) The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis. J Cell Physiol 233(2):1156–1167.  https://doi.org/10.1002/jcp.25976 CrossRefPubMedGoogle Scholar
  87. 87.
    Cianferotti L, Demay MB (2007) VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells. J Cell Biochem 101(1):80–88.  https://doi.org/10.1002/jcb.21151 CrossRefPubMedGoogle Scholar
  88. 88.
    Jin EJ, Park JH, Lee SY, Chun JS, Bang OS, Kang SS (2006) Wnt-5a is involved in TGF-beta3-stimulated chondrogenic differentiation of chick wing bud mesenchymal cells. Int J Biochem Cell Biol 38(2):183–195.  https://doi.org/10.1016/j.biocel.2005.08.013 CrossRefPubMedGoogle Scholar
  89. 89.
    Liu S, Zhang E, Yang M, Lu L (2014) Overexpression of Wnt11 promotes chondrogenic differentiation of bone marrow-derived mesenchymal stem cells in synergism with TGF-beta. Mol Cell Biochem 390(1–2):123–131.  https://doi.org/10.1007/s11010-014-1963-0 CrossRefPubMedGoogle Scholar
  90. 90.
    Hsu SH, Huang GS (2013) Substrate-dependent Wnt signaling in MSC differentiation within biomaterial-derived 3D spheroids. Biomaterials 34(20):4725–4738.  https://doi.org/10.1016/j.biomaterials.2013.03.031 CrossRefPubMedGoogle Scholar
  91. 91.
    Zhang Y, Li J, Davis ME, Pei M (2015) Delineation of in vitro chondrogenesis of human synovial stem cells following preconditioning using decellularized matrix. Acta Biomater 20:39–50.  https://doi.org/10.1016/j.actbio.2015.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Nishizuka M, Koyanagi A, Osada S, Imagawa M (2008) Wnt4 and Wnt5a promote adipocyte differentiation. FEBS Lett 582(21–22):3201–3205.  https://doi.org/10.1016/j.febslet.2008.08.011 CrossRefPubMedGoogle Scholar
  93. 93.
    Grogan SP, Olee T, Hiraoka K, Lotz MK (2008) Repression of chondrogenesis through binding of notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site. Arthritis Rheum 58(9):2754–2763.  https://doi.org/10.1002/art.23730 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Tian Y, Xu Y, Fu Q, Chang M, Wang Y, Shang X, Wan C, Marymont JV, Dong Y (2015) Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1. Mol Cell Endocrinol 403:30–38.  https://doi.org/10.1016/j.mce.2015.01.015 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Osathanon T, Subbalekha K, Sastravaha P, Pavasant P (2012) Notch signalling inhibits the adipogenic differentiation of single-cell-derived mesenchymal stem cell clones isolated from human adipose tissue. Cell Biol Int 36(12):1161–1170.  https://doi.org/10.1042/CBI20120288 CrossRefPubMedGoogle Scholar
  96. 96.
    Lai PY, Tsai CB, Tseng MJ (2013) Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes. Biochem Biophys Res Commun 430(3):1132–1139.  https://doi.org/10.1016/j.bbrc.2012.12.024 CrossRefPubMedGoogle Scholar
  97. 97.
    Garces C, Ruiz-Hidalgo MJ, Font de Mora J, Park C, Miele L, Goldstein J, Bonvini E, Porras A, Laborda J (1997) Notch-1 controls the expression of fatty acid-activated transcription factors and is required for adipogenesis. J Biol Chem 272(47):29729–29734CrossRefPubMedGoogle Scholar
  98. 98.
    Ross DA, Rao PK, Kadesch T (2004) Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol Cell Biol 24(8):3505–3513CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Ugarte F, Ryser M, Thieme S, Fierro FA, Navratiel K, Bornhauser M, Brenner S (2009) Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp Hematol 37(7):867–875.  https://doi.org/10.1016/j.exphem.2009.03.007 CrossRefPubMedGoogle Scholar
  100. 100.
    Song BQ, Chi Y, Li X, Du WJ, Han ZB, Tian JJ, Li JJ, Chen F, Wu HH, Han LX, Lu SH, Zheng YZ, Han ZC (2015) Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K/AKT/mTOR pathway. Cell Physiol Biochem 36(5):1991–2002.  https://doi.org/10.1159/000430167 CrossRefPubMedGoogle Scholar
  101. 101.
    Ba K, Yang X, Wu L, Wei X, Fu N, Fu Y, Cai X, Yao Y, Ge Y, Lin Y (2012) Jagged-1-mediated activation of notch signalling induces adipogenesis of adipose-derived stem cells. Cell Prolif 45(6):538–544.  https://doi.org/10.1111/j.1365-2184.2012.00850.x CrossRefPubMedGoogle Scholar
  102. 102.
    Li J, Hansen KC, Zhang Y, Dong C, Dinu CZ, Dzieciatkowska M, Pei M (2014) Rejuvenation of chondrogenic potential in a young stem cell microenvironment. Biomaterials 35(2):642–653.  https://doi.org/10.1016/j.biomaterials.2013.09.099 CrossRefPubMedGoogle Scholar
  103. 103.
    Xiao Y, Peperzak V, van Rijn L, Borst J, de Bruijn JD (2010) Dexamethasone treatment during the expansion phase maintains stemness of bone marrow mesenchymal stem cells. J Tissue Eng Regen Med 4(5):374–386.  https://doi.org/10.1002/term.250 CrossRefPubMedGoogle Scholar
  104. 104.
    Derfoul A, Perkins GL, Hall DJ, Tuan RS (2006) Glucocorticoids promote chondrogenic differentiation of adult human mesenchymal stem cells by enhancing expression of cartilage extracellular matrix genes. Stem Cells 24(6):1487–1495.  https://doi.org/10.1634/stemcells.2005-0415 CrossRefPubMedGoogle Scholar
  105. 105.
    Tangtrongsup S, Kisiday JD (2016) Effects of dexamethasone concentration and timing of exposure on chondrogenesis of equine bone marrow-derived mesenchymal stem cells. Cartilage 7(1):92–103.  https://doi.org/10.1177/1947603515595263 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Naito M, Ohashi A, Takahashi T (2015) Dexamethasone inhibits chondrocyte differentiation by suppression of Wnt/beta-catenin signaling in the chondrogenic cell line ATDC5. Histochem Cell Biol 144(3):261–272.  https://doi.org/10.1007/s00418-015-1334-2 CrossRefPubMedGoogle Scholar
  107. 107.
    Mouw JK, Connelly JT, Wilson CG, Michael KE, Levenston ME (2007) Dynamic compression regulates the expression and synthesis of chondrocyte-specific matrix molecules in bone marrow stromal cells. Stem Cells 25(3):655–663.  https://doi.org/10.1634/stemcells.2006-0435 CrossRefPubMedGoogle Scholar
  108. 108.
    Kurth T, Hedbom E, Shintani N, Sugimoto M, Chen FH, Haspl M, Martinovic S, Hunziker EB (2007) Chondrogenic potential of human synovial mesenchymal stem cells in alginate. Osteoarthr Cartil 15(10):1178–1189.  https://doi.org/10.1016/j.joca.2007.03.015 CrossRefPubMedGoogle Scholar
  109. 109.
    Shintani N, Hunziker EB (2011) Differential effects of dexamethasone on the chondrogenesis of mesenchymal stromal cells influence of microenvironment, tissue origin and growth factor. Eur Cells Mater 22:302–319CrossRefGoogle Scholar
  110. 110.
    Oshina H, Sotome S, Yoshii T, Torigoe I, Sugata Y, Maehara H, Marukawa E, Omura K, Shinomiya K (2007) Effects of continuous dexamethasone treatment on differentiation capabilities of bone marrow-derived mesenchymal cells. Bone 41(4):575–583.  https://doi.org/10.1016/j.bone.2007.06.022 CrossRefPubMedGoogle Scholar
  111. 111.
    Naito M, Omoteyama K, Mikami Y, Takahashi T, Takagi M (2012) Inhibition of Wnt/beta-catenin signaling by dexamethasone promotes adipocyte differentiation in mesenchymal progenitor cells, ROB-C26. Histochem Cell Biol 138(6):833–845.  https://doi.org/10.1007/s00418-012-1007-3 CrossRefPubMedGoogle Scholar
  112. 112.
    He Q, Huang HY, Zhang YY, Li X, Qian SW, Tang QQ (2012) TAZ is downregulated by dexamethasone during the differentiation of 3T3-L1 preadipocytes. Biochem Biophys Res Commun 419(3):573–577.  https://doi.org/10.1016/j.bbrc.2012.02.074 CrossRefPubMedGoogle Scholar
  113. 113.
    Wang GJ, Cui Q, Balian G (2000) The nicolas andry award. The pathogenesis and prevention of steroid-induced osteonecrosis. Clin Orthop Relat Res 370:295–310CrossRefGoogle Scholar
  114. 114.
    Mikami Y, Lee M, Irie S, Honda MJ (2011) Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells. J Cell Physiol 226(3):739–748.  https://doi.org/10.1002/jcp.22392 CrossRefPubMedGoogle Scholar
  115. 115.
    Hara ES, Ono M, Pham HT, Sonoyama W, Kubota S, Takigawa M, Matsumoto T, Young MF, Olsen BR, Kuboki T (2015) Fluocinolone acetonide is a potent synergistic factor of TGF-beta3-associated chondrogenesis of bone marrow-derived mesenchymal stem cells for articular surface regeneration. J Bone Miner Res 30(9):1585–1596.  https://doi.org/10.1002/jbmr.2502 CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Zhang YY, Li X, Qian SW, Guo L, Huang HY, He Q, Liu Y, Ma CG, Tang QQ (2012) Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis. Mol Endocrinol 26(5):798–808.  https://doi.org/10.1210/me.2011-1287 CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Li J, Zhang N, Huang X, Xu J, Fernandes JC, Dai K, Zhang X (2013) Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation. Cell Death Disease 4:e832.  https://doi.org/10.1038/cddis.2013.348 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Correa D, Somoza RA, Lin P, Greenberg S, Rom E, Duesler L, Welter JF, Yayon A, Caplan AI (2015) Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation. Osteoarthr Res Soc 23(3):443–453.  https://doi.org/10.1016/j.joca.2014.11.013 CrossRefGoogle Scholar
  119. 119.
    Le Blanc S, Simann M, Jakob F, Schutze N, Schilling T (2015) Fibroblast growth factors 1 and 2 inhibit adipogenesis of human bone marrow stromal cells in 3D collagen gels. Exp Cell Res 338(2):136–148.  https://doi.org/10.1016/j.yexcr.2015.09.009 CrossRefPubMedGoogle Scholar
  120. 120.
    Pizzute T, Li JT, Zhang Y, Davis ME, Pei M (2016) Fibroblast growth factor ligand dependent proliferation and chondrogenic differentiation of synovium-derived stem cells and concomitant adaptation of wnt/mitogen-activated protein kinase signals. Tissue Eng Pt A 22(15–16):1036–1046CrossRefGoogle Scholar
  121. 121.
    Solchaga LA, Penick K, Goldberg VM, Caplan AI, Welter JF (2010) Fibroblast growth factor-2 enhances proliferation and delays loss of chondrogenic potential in human adult bone-marrow-derived mesenchymal stem cells. Tissue Eng Part A 16(3):1009–1019CrossRefPubMedGoogle Scholar
  122. 122.
    Kim JH, Lee MC, Seong SC, Park KH, Lee S (2011) Enhanced Proliferation and chondrogenic differentiation of human synovium-derived stem cells expanded with basic fibroblast growth factor. Tissue Eng Part A 17(7–8):991–1002CrossRefPubMedGoogle Scholar
  123. 123.
    Solchaga LA, Penick K, Porter JD, Goldberg VM, Caplan AI, Welter JF (2005) FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells. J Cell Physiol 203(2):398–409CrossRefPubMedGoogle Scholar
  124. 124.
    Buckley CT, Kelly DJ (2012) Expansion in the presence of FGF-2 enhances the functional development of cartilaginous tissues engineered using infrapatellar fat pad derived MSCs. J Mech Behav Biomed 11:102–111CrossRefGoogle Scholar
  125. 125.
    Cheng T, Yang C, Weber N, Kim HT, Kuo AC (2012) Fibroblast growth factor 2 enhances the kinetics of mesenchymal stem cell chondrogenesis. Biochem Biophys Res Commun 426(4):544–550CrossRefPubMedGoogle Scholar
  126. 126.
    Bianchessi M, Chen Y, Durgam S, Pondenis H, Stewart M (2016) Effect of fibroblast growth factor 2 on equine synovial fluid chondroprogenitor expansion and chondrogenesis. Stem Cells Int 2016:9364974.  https://doi.org/10.1155/2016/9364974 CrossRefPubMedGoogle Scholar
  127. 127.
    Coipeau P, Rosset P, Langonne A, Gaillard J, Delorme B, Rico A, Domenech J, Charbord P, Sensebe L (2009) Impaired differentiation potential of human trabecular bone mesenchymal stromal cells from elderly patients. Cytotherapy 11(5):584–594CrossRefPubMedGoogle Scholar
  128. 128.
    Weiss S, Hennig T, Bock R, Steck E, Richter W (2010) Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. J Cell Physiol 223(1):84–93.  https://doi.org/10.1002/jcp.22013 CrossRefPubMedGoogle Scholar
  129. 129.
    Hildner F, Peterbauer A, Wolbank S, Nurnberger S, Marlovits S, Redl H, van Griensven M, Gabriel C (2010) FGF-2 abolishes the chondrogenic effect of combined BMP-6 and TGF-beta in human adipose derived stem cells. J Biomed Mater Res, Part A 94(3):978–987.  https://doi.org/10.1002/jbm.a.32761 CrossRefGoogle Scholar
  130. 130.
    Bosetti M, Boccafoschi F, Leigheb M, Bianchi AE, Cannas M (2012) Chondrogenic induction of human mesenchymal stem cells using combined growth factors for cartilage tissue engineering. J Tissue Eng Regen Med 6(3):205–213.  https://doi.org/10.1002/term.416 CrossRefPubMedGoogle Scholar
  131. 131.
    Hutley L, Shurety W, Newell F, McGeary R, Pelton N, Grant J, Herington A, Cameron D, Whitehead J, Prins J (2004) Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes 53(12):3097–3106CrossRefPubMedGoogle Scholar
  132. 132.
    Neubauer M, Fischbach C, Bauer-Kreisel P, Lieb E, Hacker M, Tessmar J, Schulz MB, Goepferich A, Blunk T (2004) Basic fibroblast growth factor enhances PPARgamma ligand-induced adipogenesis of mesenchymal stem cells. FEBS Lett 577(1–2):277–283.  https://doi.org/10.1016/j.febslet.2004.10.020 CrossRefPubMedGoogle Scholar
  133. 133.
    Inoue S, Hori Y, Hirano Y, Inamoto T, Tabata Y (2005) Effect of culture substrate and fibroblast growth factor addition on the proliferation and differentiation of human adipo-stromal cells. J Biomater Sci Polym Ed 16(1):57–77CrossRefPubMedGoogle Scholar
  134. 134.
    Kakudo N, Shimotsuma A, Kusumoto K (2007) Fibroblast growth factor-2 stimulates adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun 359(2):239–244.  https://doi.org/10.1016/j.bbrc.2007.05.070 CrossRefPubMedGoogle Scholar
  135. 135.
    Prusty D, Park BH, Davis KE, Farmer SR (2002) Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor gamma (PPARgamma) and C/EBPalpha gene expression during the differentiation of 3T3-L1 preadipocytes. J Biol Chem 277(48):46226–46232.  https://doi.org/10.1074/jbc.M207776200 CrossRefPubMedGoogle Scholar
  136. 136.
    Kalomoiris S, Cicchetto AC, Lakatos K, Nolta JA, Fierro FA (2016) Fibroblast growth factor 2 regulates high mobility group A2 expression in human bone marrow-derived mesenchymal stem cells. J Cell Biochem 117(9):2128–2137.  https://doi.org/10.1002/jcb.25519 CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Luo X, Hutley LJ, Webster JA, Kim YH, Liu DF, Newell FS, Widberg CH, Bachmann A, Turner N, Schmitz-Peiffer C, Prins JB, Yang GS, Whitehead JP (2012) Identification of BMP and activin membrane-bound inhibitor (BAMBI) as a potent negative regulator of adipogenesis and modulator of autocrine/paracrine adipogenic factors. Diabetes 61(1):124–136.  https://doi.org/10.2337/db11-0998 CrossRefPubMedGoogle Scholar
  138. 138.
    Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61(2):203–212CrossRefPubMedGoogle Scholar
  139. 139.
    Frisch J, Venkatesan JK, Rey-Rico A, Schmitt G, Madry H, Cucchiarini M (2014) Influence of insulin-like growth factor I overexpression via recombinant adeno-associated vector gene transfer upon the biological activities and differentiation potential of human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 5(4):103.  https://doi.org/10.1186/scrt491 CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Frisch J, Rey-Rico A, Venkatesan JK, Schmitt G, Madry H, Cucchiarini M (2015) Chondrogenic differentiation processes in human bone marrow aspirates upon rAAV-mediated gene transfer and overexpression of the insulin-like growth factor I. Tissue Eng Part A 21(17–18):2460–2471.  https://doi.org/10.1089/ten.TEA.2014.0679 CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Giorgetti S, Ballotti R, Kowalski-Chauvel A, Tartare S, Van Obberghen E (1993) The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro. J Biol Chem 268(10):7358–7364PubMedGoogle Scholar
  142. 142.
    Phornphutkul C, Wu KY, Yang X, Chen Q, Gruppuso PA (2004) Insulin-like growth factor-I signaling is modified during chondrocyte differentiation. J Endocrinol 183(3):477–486.  https://doi.org/10.1677/joe.1.05873 CrossRefPubMedGoogle Scholar
  143. 143.
    Starkman BG, Cravero JD, Delcarlo M, Loeser RF (2005) IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J 389(Pt 3):723–729.  https://doi.org/10.1042/BJ20041636 CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Boney CM, Smith RM, Gruppuso PA (1998) Modulation of insulin-like growth factor I mitogenic signaling in 3T3-L1 preadipocyte differentiation. Endocrinology 139(4):1638–1644.  https://doi.org/10.1210/endo.139.4.5920 CrossRefPubMedGoogle Scholar
  145. 145.
    Boney CM, Gruppuso PA, Faris RA, Frackelton AR Jr (2000) The critical role of Shc in insulin-like growth factor-I-mediated mitogenesis and differentiation in 3T3-L1 preadipocytes. Mol Endocrinol 14(6):805–813.  https://doi.org/10.1210/mend.14.6.0487 CrossRefPubMedGoogle Scholar
  146. 146.
    Oh CD, Chun JS (2003) Signaling mechanisms leading to the regulation of differentiation and apoptosis of articular chondrocytes by insulin-like growth factor-1. J Biol Chem 278(38):36563–36571.  https://doi.org/10.1074/jbc.M304857200 CrossRefPubMedGoogle Scholar
  147. 147.
    McMahon LA, Prendergast PJ, Campbell VA (2008) A comparison of the involvement of p38, ERK1/2 and PI3K in growth factor-induced chondrogenic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun 368(4):990–995.  https://doi.org/10.1016/j.bbrc.2008.01.160 CrossRefPubMedGoogle Scholar
  148. 148.
    Zhang L, Grennan-Jones F, Draman MS, Lane C, Morris D, Dayan CM, Tee AR, Ludgate M (2014) Possible targets for nonimmunosuppressive therapy of Graves’ orbitopathy. J Clin Endocrinol Metab 99(7):E1183–E1190.  https://doi.org/10.1210/jc.2013-4182 CrossRefPubMedGoogle Scholar
  149. 149.
    Miki H, Yamauchi T, Suzuki R, Komeda K, Tsuchida A, Kubota N, Terauchi Y, Kamon J, Kaburagi Y, Matsui J, Akanuma Y, Nagai R, Kimura S, Tobe K, Kadowaki T (2001) Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol 21(7):2521–2532.  https://doi.org/10.1128/MCB.21.7.2521-2532.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Viti F, Landini M, Mezzelani A, Petecchia L, Milanesi L, Scaglione S (2016) Osteogenic differentiation of MSC through calcium signaling activation: transcriptomics and functional analysis. PLoS One 11(2):e0148173.  https://doi.org/10.1371/journal.pone.0148173 CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Kawano S, Shoji S, Ichinose S, Yamagata K, Tagami M, Hiraoka M (2002) Characterization of Ca(2 +) signaling pathways in human mesenchymal stem cells. Cell Calcium 32(4):165–174CrossRefPubMedGoogle Scholar
  152. 152.
    Dry H, Jorgenson K, Ando W, Hart DA, Frank CB, Sen A (2013) Effect of calcium on the proliferation kinetics of synovium-derived mesenchymal stromal cells. Cytotherapy 15(7):805–819.  https://doi.org/10.1016/j.jcyt.2013.01.011 CrossRefPubMedGoogle Scholar
  153. 153.
    Mellor LF, Mohiti-Asli M, Williams J, Kannan A, Dent MR, Guilak F, Loboa EG (2015) Extracellular calcium modulates chondrogenic and osteogenic differentiation of human adipose-derived stem cells: a novel approach for osteochondral tissue engineering using a single stem cell source. Tissue Eng Part A 21(17–18):2323–2333.  https://doi.org/10.1089/ten.TEA.2014.0572 CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Parate D, Franco-Obregon A, Frohlich J, Beyer C, Abbas AA, Kamarul T, Hui JHP, Yang Z (2017) Enhancement of mesenchymal stem cell chondrogenesis with short-term low intensity pulsed electromagnetic fields. Sci Rep 7(1):9421.  https://doi.org/10.1038/s41598-017-09892-w CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Steward AJ, Kelly DJ, Wagner DR (2014) The role of calcium signalling in the chondrogenic response of mesenchymal stem cells to hydrostatic pressure. Eur Cells Mater 28:358–371CrossRefGoogle Scholar
  156. 156.
    Kwon HJ, Lee GS, Chun H (2016) Electrical stimulation drives chondrogenesis of mesenchymal stem cells in the absence of exogenous growth factors. Sci Rep 6:39302.  https://doi.org/10.1038/srep39302 CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Holzer P (2011) Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther 131(1):142–170.  https://doi.org/10.1016/j.pharmthera.2011.03.006 CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Pall ML (2013) Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. J Cell Mol Med 17(8):958–965.  https://doi.org/10.1111/jcmm.12088 CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Shi H, Halvorsen YD, Ellis PN, Wilkison WO, Zemel MB (2000) Role of intracellular calcium in human adipocyte differentiation. Physiol Genom 3(2):75–82.  https://doi.org/10.1152/physiolgenomics.2000.3.2.75 CrossRefGoogle Scholar
  160. 160.
    Jensen B, Farach-Carson MC, Kenaley E, Akanbi KA (2004) High extracellular calcium attenuates adipogenesis in 3T3-L1 preadipocytes. Exp Cell Res 301(2):280–292.  https://doi.org/10.1016/j.yexcr.2004.08.030 CrossRefPubMedGoogle Scholar
  161. 161.
    Hashimoto R, Katoh Y, Miyamoto Y, Itoh S, Daida H, Nakazato Y, Okada T (2015) Increased extracellular and intracellular Ca(2)(+) lead to adipocyte accumulation in bone marrow stromal cells by different mechanisms. Biochem Biophys Res Commun 457(4):647–652.  https://doi.org/10.1016/j.bbrc.2015.01.042 CrossRefPubMedGoogle Scholar
  162. 162.
    Hashimoto R, Katoh Y, Nakamura K, Itoh S, Iesaki T, Daida H, Nakazato Y, Okada T (2012) Enhanced accumulation of adipocytes in bone marrow stromal cells in the presence of increased extracellular and intracellular [Ca(2)(+)]. Biochem Biophys Res Commun 423(4):672–678.  https://doi.org/10.1016/j.bbrc.2012.06.010 CrossRefPubMedGoogle Scholar
  163. 163.
    Hashimoto R, Katoh Y, Miyamoto Y, Nakamura K, Itoh S, Daida H, Nakazato Y, Okada T (2017) High extracellular Ca(2 +) enhances the adipocyte accumulation of bone marrow stromal cells through a decrease in cAMP. Cell Calcium 67:74–80.  https://doi.org/10.1016/j.ceca.2017.08.006 CrossRefPubMedGoogle Scholar
  164. 164.
    Zhang F, Ye J, Meng Y, Ai W, Su H, Zheng J, Liu F, Zhu X, Wang L, Gao P, Shu G, Jiang Q, Wang S (2018) Calcium supplementation enhanced adipogenesis and improved glucose homeostasis through activation of Camkii and PI3K/Akt signaling pathway in porcine bone marrow mesenchymal stem cells (pBMSCs) and mice fed high fat diet (HFD). Cellular Physiol Biochem 51(1):154–172.  https://doi.org/10.1159/000495171 CrossRefGoogle Scholar
  165. 165.
    Bae YK, Kwon JH, Kim M, Kim GH, Choi SJ, Oh W, Yang YS, Jin HJ, Jeon HB (2018) Intracellular Calcium determines the adipogenic differentiation potential of human umbilical cord blood-derived mesenchymal stem cells via the Wnt5a/beta-Catenin signaling pathway. Stem Cells Int 2018:6545071.  https://doi.org/10.1155/2018/6545071 CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Gao L, McBeath R, Chen CS (2010) Stem cell shape regulates a chondrogenic versus myogenic fate through Rac1 and N-cadherin. Stem Cells 28(3):564–572.  https://doi.org/10.1002/stem.308 CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Shao HJ, Ho CC, Lee YT, Chen CS, Wang JH, Young TH (2012) Chondrogenesis of human bone marrow mesenchymal cells by transforming growth factors beta1 through cell shape changes on controlled biomaterials. J Biomed Mater Res, Part A 100(12):3344–3352.  https://doi.org/10.1002/jbm.a.34291 CrossRefGoogle Scholar
  168. 168.
    Chang KH, Liao HT, Chen JP (2013) Preparation and characterization of gelatin/hyaluronic acid cryogels for adipose tissue engineering: in vitro and in vivo studies. Acta Biomater 9(11):9012–9026.  https://doi.org/10.1016/j.actbio.2013.06.046 CrossRefPubMedGoogle Scholar
  169. 169.
    Mathieu PS, Loboa EG (2012) Cytoskeletal and focal adhesion influences on mesenchymal stem cell shape, mechanical properties, and differentiation down osteogenic, adipogenic, and chondrogenic pathways. Tissue Eng Part B Rev 18(6):436–444.  https://doi.org/10.1089/ten.TEB.2012.0014 CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6(4):483–495CrossRefPubMedGoogle Scholar
  171. 171.
    Zhang Y, Chen S, Pei M (2016) Biomechanical signals guiding stem cell cartilage engineering: from molecular adaption to tissue functionality. Eur Cells Mater 31:59–78CrossRefGoogle Scholar
  172. 172.
    Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689.  https://doi.org/10.1016/j.cell.2006.06.044 CrossRefPubMedGoogle Scholar
  173. 173.
    Schwarz S, Elsaesser AF, Koerber L, Goldberg-Bockhorn E, Seitz AM, Bermueller C, Durselen L, Ignatius A, Breiter R, Rotter N (2015) Processed xenogenic cartilage as innovative biomatrix for cartilage tissue engineering: effects on chondrocyte differentiation and function. J Tissue Eng Regen Med 9(12):E239–E251.  https://doi.org/10.1002/term.1650 CrossRefPubMedGoogle Scholar
  174. 174.
    Garrigues NW, Little D, Sanchez-Adams J, Ruch DS, Guilak F (2014) Electrospun cartilage-derived matrix scaffolds for cartilage tissue engineering. J Biomed Mater Res, Part A 102(11):3998–4008.  https://doi.org/10.1002/jbm.a.35068 CrossRefGoogle Scholar
  175. 175.
    Park JS, Chu JS, Tsou AD, Diop R, Tang Z, Wang A, Li S (2011) The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-beta. Biomaterials 32(16):3921–3930.  https://doi.org/10.1016/j.biomaterials.2011.02.019 CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Young DA, Choi YS, Engler AJ, Christman KL (2013) Stimulation of adipogenesis of adult adipose-derived stem cells using substrates that mimic the stiffness of adipose tissue. Biomaterials 34(34):8581–8588.  https://doi.org/10.1016/j.biomaterials.2013.07.103 CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Hwang JH, Byun MR, Kim AR, Kim KM, Cho HJ, Lee YH, Kim J, Jeong MG, Hwang ES, Hong JH (2015) Extracellular matrix stiffness regulates osteogenic differentiation through MAPK activation. PLoS One 10(8):e0135519.  https://doi.org/10.1371/journal.pone.0135519 CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Ye K, Cao L, Li S, Yu L, Ding J (2016) Interplay of matrix stiffness and cell-cell contact in regulating differentiation of stem cells. ACS Appl Mater Interfaces 8(34):21903–21913.  https://doi.org/10.1021/acsami.5b09746 CrossRefPubMedGoogle Scholar
  179. 179.
    Hendriks JA, Moroni L, Riesle J, de Wijn JR, van Blitterswijk CA (2013) The effect of scaffold-cell entrapment capacity and physico-chemical properties on cartilage regeneration. Biomaterials 34(17):4259–4265.  https://doi.org/10.1016/j.biomaterials.2013.02.060 CrossRefPubMedGoogle Scholar
  180. 180.
    Younesi M, Goldberg VM, Akkus O (2016) A micro-architecturally biomimetic collagen template for mesenchymal condensation based cartilage regeneration. Acta Biomater 30:212–221.  https://doi.org/10.1016/j.actbio.2015.11.024 CrossRefPubMedGoogle Scholar
  181. 181.
    Muller WE, Neufurth M, Wang S, Tolba E, Schroder HC, Wang X (2016) Morphogenetically active scaffold for osteochondral repair (polyphosphate/alginate/N, O-carboxymethyl chitosan). Eur Cells Mater 31:174–190CrossRefGoogle Scholar
  182. 182.
    Kim JS, Choi JS, Cho YW (2017) Cell-free hydrogel system based on a tissue-specific extracellular matrix for in situ adipose tissue regeneration. ACS Appl Mater Interfaces 9(10):8581–8588.  https://doi.org/10.1021/acsami.6b16783 CrossRefPubMedGoogle Scholar
  183. 183.
    Zhao W, Li X, Liu X, Zhang N, Wen X (2014) Effects of substrate stiffness on adipogenic and osteogenic differentiation of human mesenchymal stem cells. Mater Sci Eng C 40:316–323.  https://doi.org/10.1016/j.msec.2014.03.048 CrossRefGoogle Scholar
  184. 184.
    Shoham N, Girshovitz P, Katzengold R, Shaked NT, Benayahu D, Gefen A (2014) Adipocyte stiffness increases with accumulation of lipid droplets. Biophys J 106(6):1421–1431.  https://doi.org/10.1016/j.bpj.2014.01.045 CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Lim YB, Kang SS, Park TK, Lee YS, Chun JS, Sonn JK (2000) Disruption of actin cytoskeleton induces chondrogenesis of mesenchymal cells by activating protein kinase C-alpha signaling. Biochem Biophys Res Commun 273(2):609–613.  https://doi.org/10.1006/bbrc.2000.2987 CrossRefPubMedGoogle Scholar
  186. 186.
    Woods A, Beier F (2006) RhoA/ROCK signaling regulates chondrogenesis in a context-dependent manner. J Biol Chem 281(19):13134–13140.  https://doi.org/10.1074/jbc.M509433200 CrossRefPubMedGoogle Scholar
  187. 187.
    Campbell JJ, Lee DA, Bader DL (2006) Dynamic compressive strain influences chondrogenic gene expression in human mesenchymal stem cells. Biorheology 43(4):455–470PubMedGoogle Scholar
  188. 188.
    Kupcsik L, Stoddart MJ, Li Z, Benneker LM, Alini M (2010) Improving chondrogenesis: potential and limitations of SOX9 gene transfer and mechanical stimulation for cartilage tissue engineering. Tissue Eng Part A 16(6):1845–1855.  https://doi.org/10.1089/ten.TEA.2009.0531 CrossRefPubMedGoogle Scholar
  189. 189.
    Li Z, Kupcsik L, Yao SJ, Alini M, Stoddart MJ (2010) Mechanical load modulates chondrogenesis of human mesenchymal stem cells through the TGF-beta pathway. J Cell Mol Med 14(6A):1338–1346.  https://doi.org/10.1111/j.1582-4934.2009.00780.x CrossRefPubMedGoogle Scholar
  190. 190.
    Zhang T, Wen F, Wu Y, Goh GS, Ge Z, Tan LP, Hui JH, Yang Z (2015) Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression. Biomaterials 38:72–85.  https://doi.org/10.1016/j.biomaterials.2014.10.010 CrossRefPubMedGoogle Scholar
  191. 191.
    Bian L, Zhai DY, Zhang EC, Mauck RL, Burdick JA (2012) Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng Part A 18(7–8):715–724.  https://doi.org/10.1089/ten.TEA.2011.0455 CrossRefPubMedGoogle Scholar
  192. 192.
    Hossain MG, Iwata T, Mizusawa N, Shima SW, Okutsu T, Ishimoto K, Yoshimoto K (2010) Compressive force inhibits adipogenesis through COX-2-mediated down-regulation of PPARgamma2 and C/EBPalpha. J Biosci Bioeng 109(3):297–303.  https://doi.org/10.1016/j.jbiosc.2009.09.003 CrossRefPubMedGoogle Scholar
  193. 193.
    Arnsdorf EJ, Tummala P, Kwon RY, Jacobs CR (2009) Mechanically induced osteogenic differentiation–the role of RhoA, ROCKII and cytoskeletal dynamics. J Cell Sci 122(Pt 4):546–553.  https://doi.org/10.1242/jcs.036293 CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Zhong W, Tian K, Zheng X, Li L, Zhang W, Wang S, Qin J (2013) Mesenchymal stem cell and chondrocyte fates in a multishear microdevice are regulated by yes-associated protein. Stem Cells Dev 22(14):2083–2093.  https://doi.org/10.1089/scd.2012.0685 CrossRefPubMedGoogle Scholar
  195. 195.
    Khan WS, Adesida AB, Hardingham TE (2007) Hypoxic conditions increase hypoxia-inducible transcription factor 2alpha and enhance chondrogenesis in stem cells from the infrapatellar fat pad of osteoarthritis patients. Arthritis Res Ther 9(3):R55.  https://doi.org/10.1186/ar2211 CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Kanichai M, Ferguson D, Prendergast PJ, Campbell VA (2008) Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: a role for AKT and hypoxia-inducible factor (HIF)-1alpha. J Cell Physiol 216(3):708–715.  https://doi.org/10.1002/jcp.21446 CrossRefPubMedGoogle Scholar
  197. 197.
    Khan WS, Adesida AB, Tew SR, Lowe ET, Hardingham TE (2010) Bone marrow-derived mesenchymal stem cells express the pericyte marker 3G5 in culture and show enhanced chondrogenesis in hypoxic conditions. J Orthop Res 28(6):834–840.  https://doi.org/10.1002/jor.21043 CrossRefPubMedGoogle Scholar
  198. 198.
    Adesida AB, Mulet-Sierra A, Jomha NM (2012) Hypoxia mediated isolation and expansion enhances the chondrogenic capacity of bone marrow mesenchymal stromal cells. Stem Cell Res Ther 3(2):9.  https://doi.org/10.1186/scrt100 CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Merceron C, Vinatier C, Portron S, Masson M, Amiaud J, Guigand L, Cherel Y, Weiss P, Guicheux J (2010) Differential effects of hypoxia on osteochondrogenic potential of human adipose-derived stem cells. Am J Physiol Cell Physiol 298(2):C355–C364.  https://doi.org/10.1152/ajpcell.00398.2009 CrossRefPubMedGoogle Scholar
  200. 200.
    Cicione C, Muinos-Lopez E, Hermida-Gomez T, Fuentes-Boquete I, Diaz-Prado S, Blanco FJ (2013) Effects of severe hypoxia on bone marrow mesenchymal stem cells differentiation potential. Stem Cells Int 2013:232896.  https://doi.org/10.1155/2013/232896 CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Yun Z, Maecker HL, Johnson RS, Giaccia AJ (2002) Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell 2(3):331–341CrossRefPubMedGoogle Scholar
  202. 202.
    Kim KH, Song MJ, Chung J, Park H, Kim JB (2005) Hypoxia inhibits adipocyte differentiation in a HDAC-independent manner. Biochem Biophys Res Commun 333(4):1178–1184.  https://doi.org/10.1016/j.bbrc.2005.06.023 CrossRefPubMedGoogle Scholar
  203. 203.
    Gentil C, Le Jan S, Philippe J, Leibowitch J, Sonigo P, Germain S, Pietri-Rouxel F (2006) Is oxygen a key factor in the lipodystrophy phenotype? Lipids Health Disease 5:27.  https://doi.org/10.1186/1476-511X-5-27 CrossRefGoogle Scholar
  204. 204.
    Itoigawa Y, Kishimoto KN, Okuno H, Sano H, Kaneko K, Itoi E (2010) Hypoxia induces adipogenic differentitation of myoblastic cell lines. Biochem Biophys Res Commun 399(4):721–726.  https://doi.org/10.1016/j.bbrc.2010.08.007 CrossRefPubMedGoogle Scholar
  205. 205.
    Weiszenstein M, Musutova M, Plihalova A, Westlake K, Elkalaf M, Koc M, Prochazka A, Pala J, Gulati S, Trnka J, Polak J (2016) Adipogenesis, lipogenesis and lipolysis is stimulated by mild but not severe hypoxia in 3T3-L1 cells. Biochem Biophys Res Commun 478(2):727–732.  https://doi.org/10.1016/j.bbrc.2016.08.015 CrossRefPubMedGoogle Scholar
  206. 206.
    Jiang C, Sun J, Dai Y, Cao P, Zhang L, Peng S, Zhou Y, Li G, Tang J, Xiang J (2015) HIF-1A and C/EBPs transcriptionally regulate adipogenic differentiation of bone marrow-derived MSCs in hypoxia. Stem Cell Res Ther 6:21.  https://doi.org/10.1186/s13287-015-0014-4 CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Fehrer C, Brunauer R, Laschober G, Unterluggauer H, Reitinger S, Kloss F, Gully C, Gassner R, Lepperdinger G (2007) Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan. Aging Cell 6(6):745–757.  https://doi.org/10.1111/j.1474-9726.2007.00336.x CrossRefPubMedGoogle Scholar
  208. 208.
    Valorani MG, Germani A, Otto WR, Harper L, Biddle A, Khoo CP, Lin WR, Hawa MI, Tropel P, Patrizi MP, Pozzilli P, Alison MR (2010) Hypoxia increases Sca-1/CD44 co-expression in murine mesenchymal stem cells and enhances their adipogenic differentiation potential. Cell Tissue Res 341(1):111–120.  https://doi.org/10.1007/s00441-010-0982-8 CrossRefPubMedGoogle Scholar
  209. 209.
    Valorani MG, Montelatici E, Germani A, Biddle A, D’Alessandro D, Strollo R, Patrizi MP, Lazzari L, Nye E, Otto WR, Pozzilli P, Alison MR (2012) Pre-culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials. Cell Prolif 45(3):225–238.  https://doi.org/10.1111/j.1365-2184.2012.00817.x CrossRefPubMedGoogle Scholar
  210. 210.
    Ranera B, Remacha AR, Alvarez-Arguedas S, Castiella T, Vazquez FJ, Romero A, Zaragoza P, Martin-Burriel I, Rodellar C (2013) Expansion under hypoxic conditions enhances the chondrogenic potential of equine bone marrow-derived mesenchymal stem cells. Vet J 195(2):248–251.  https://doi.org/10.1016/j.tvjl.2012.06.008 CrossRefPubMedGoogle Scholar
  211. 211.
    Duval E, Bauge C, Andriamanalijaona R, Benateau H, Leclercq S, Dutoit S, Poulain L, Galera P, Boumediene K (2012) Molecular mechanism of hypoxia-induced chondrogenesis and its application in in vivo cartilage tissue engineering. Biomaterials 33(26):6042–6051.  https://doi.org/10.1016/j.biomaterials.2012.04.061 CrossRefPubMedGoogle Scholar
  212. 212.
    Lee HH, Chang CC, Shieh MJ, Wang JP, Chen YT, Young TH, Hung SC (2013) Hypoxia enhances chondrogenesis and prevents terminal differentiation through PI3K/Akt/FoxO dependent anti-apoptotic effect. Sci Rep 3:2683.  https://doi.org/10.1038/srep02683 CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Lin Q, Gao Z, Alarcon RM, Ye J, Yun Z (2009) A role of miR-27 in the regulation of adipogenesis. The FEBS J 276(8):2348–2358CrossRefPubMedGoogle Scholar
  214. 214.
    Vacanti V, Kong E, Suzuki G, Sato K, Canty JM, Lee T (2005) Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture. J Cell Physiol 205(2):194–201.  https://doi.org/10.1002/jcp.20376 CrossRefPubMedGoogle Scholar
  215. 215.
    Erickson IE, van Veen SC, Sengupta S, Kestle SR, Mauck RL (2011) Cartilage matrix formation by bovine mesenchymal stem cells in three-dimensional culture is age-dependent. Clin Orthop Relat Res 469(10):2744–2753.  https://doi.org/10.1007/s11999-011-1869-z CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Tan Q, Lui PP, Rui YF (2012) Effect of in vitro passaging on the stem cell-related properties of tendon-derived stem cells-implications in tissue engineering. Stem Cells Dev 21(5):790–800.  https://doi.org/10.1089/scd.2011.0160 CrossRefPubMedGoogle Scholar
  217. 217.
    Bertolo A, Mehr M, Janner-Jametti T, Graumann U, Aebli N, Baur M, Ferguson SJ, Stoyanov JV (2016) An in vitro expansion score for tissue-engineering applications with human bone marrow-derived mesenchymal stem cells. J Tissue Eng Regen Med 10(2):149–161.  https://doi.org/10.1002/term.1734 CrossRefPubMedGoogle Scholar
  218. 218.
    Jiang Y, Mishima H, Sakai S, Liu YK, Ohyabu Y, Uemura T (2008) Gene expression analysis of major lineage-defining factors in human bone marrow cells: effect of aging, gender, and age-related disorders. J Orthop Res 26(7):910–917.  https://doi.org/10.1002/jor.20623 CrossRefPubMedGoogle Scholar
  219. 219.
    Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3(6):379–389.  https://doi.org/10.1111/j.1474-9728.2004.00127.x CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7:14.  https://doi.org/10.1186/1471-2121-7-14 CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Conget PA, Minguell JJ (1999) Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol 181(1):67–73.  https://doi.org/10.1002/(SICI)1097-4652(199910)181:1%3c67:AID-JCP7%3e3.0.CO;2-C CrossRefPubMedGoogle Scholar
  222. 222.
    Zhao Y, Waldman SD, Flynn LE (2012) The effect of serial passaging on the proliferation and differentiation of bovine adipose-derived stem cells. Cells, Tissues, Organs 195(5):414–427.  https://doi.org/10.1159/000329254 CrossRefPubMedGoogle Scholar
  223. 223.
    Stenderup K, Justesen J, Clausen C, Kassem M (2003) Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33(6):919–926CrossRefPubMedGoogle Scholar
  224. 224.
    Morse D, Choi AM (2002) Heme oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol 27(1):8–16.  https://doi.org/10.1165/ajrcmb.27.1.4862 CrossRefPubMedGoogle Scholar
  225. 225.
    Vanella L, Sodhi K, Kim DH, Puri N, Maheshwari M, Hinds TD, Bellner L, Goldstein D, Peterson SJ, Shapiro JI, Abraham NG (2013) Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade. Stem Cell Rese Therapy 4(2):28.  https://doi.org/10.1186/scrt176 CrossRefGoogle Scholar
  226. 226.
    Park EJ, Koo OJ, Lee BC (2015) Overexpressed human heme Oxygenase-1 decreases adipogenesis in pigs and porcine adipose-derived stem cells. Biochem Biophys Res Commun 467(4):935–940.  https://doi.org/10.1016/j.bbrc.2015.10.040 CrossRefPubMedGoogle Scholar
  227. 227.
    Hamedi-Asl P, Halabian R, Bahmani P, Mohammadipour M, Mohammadzadeh M, Roushandeh AM, Jahanian-Najafabadi A, Kuwahara Y, Roudkenar MH (2012) Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses. Cell Stress Chaperones 17(2):181–190.  https://doi.org/10.1007/s12192-011-0298-y CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Stem Cell and Tissue Engineering Laboratory, Department of OrthopaedicsWest Virginia UniversityMorgantownUSA
  2. 2.Department of Sports Medicine and Adult Reconstructive Surgery, School of Medicine, Drum Tower HospitalNanjing UniversityNanjingPeople’s Republic of China
  3. 3.Department of OrthopaedicsChengdu Military General HospitalChengduPeople’s Republic of China
  4. 4.Robert C. Byrd Health Sciences Center, WVU Cancer InstituteWest Virginia UniversityMorgantownUSA

Personalised recommendations

Cite article

Buy options