Skip to main content

Advertisement

SpringerLink
Log in

The Emerging Role of Glucose Metabolism in Cartilage Development

  • Skeletal Development (R Marcucio and J Feng, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Proper cartilage development is critical to bone formation during endochondral ossification. This review highlights the current understanding of various aspects of glucose metabolism in chondrocytes during cartilage development.

Recent Findings

Recent studies indicate that chondrocytes transdifferentiate into osteoblasts and bone marrow stromal cells during endochondral ossification. In cartilage development, signaling molecules, including IGF2 and BMP2, tightly control glucose uptake and utilization in a stage-specific manner. Perturbation of glucose metabolism alters the course of chondrocyte maturation, suggesting a key role for glucose metabolism during endochondral ossification.

Summary

During prenatal and postnatal growth, chondrocytes experience bursts of nutrient availability and energy expenditure, which demand sophisticated control of the glucose-dependent processes of cartilage matrix production, cell proliferation, and hypertrophy. Investigating the regulation of glucose metabolism may therefore lead to a unifying mechanism for signaling events in cartilage development and provide insight into causes of skeletal growth abnormalities.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Kobayashi T, Kronenberg HM. Overview of skeletal development. In: Hilton MJ, editor. Skeletal development and repair. Methods in molecular biology. Totowa, NJ: Humana Press; 2014.

    Google Scholar 

  2. Lefebvre V, Smits P. Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res C Embryo Today. 2005;75(3):200–12. https://doi.org/10.1002/bdrc.20048.

    Article  CAS  PubMed  Google Scholar 

  3. de Crombrugghe B, Lefebvre V, Nakashima K. Regulatory mechanisms in the pathways of cartilage and bone formation. Curr Opin Cell Biol. 2001;13:721–7.

    Article  PubMed  Google Scholar 

  4. Mizuhashi K, Ono W, Matsushita Y, Sakagami N, Takahashi A, Saunders TL, et al. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature. 2018;563:254–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abad V, Meyers JL, Weise M, Gafni RI, Barnes KM, Nilsson O, et al. The role of the resting zone in growth plate chondrogenesis. Endocrinology. 2002;143(5):1851–7.

    Article  CAS  PubMed  Google Scholar 

  6. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423:332–6.

    Article  CAS  PubMed  Google Scholar 

  7. Hinton RJ, Jing Y, Jing J, Feng JQ. Roles of chondrocytes in endochondral bone formation and fracture repair. J Dent Res. 2017;96(1):23–30. https://doi.org/10.1177/0022034516668321.

    Article  CAS  PubMed  Google Scholar 

  8. Jing Y, Jing J, Ye L, Liu X, Harris SE, Hinton RJ, et al. Chondrogenesis and osteogenesis are one continuous developmental and lineage defined biological process. Sci Rep. 2017;7:10020. https://doi.org/10.1038/s41598-017-10048-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang L, Tsang KY, Tang HC, Chan D, Cheah KSE. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111(33):12097–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tsang KY, Chan D, Cheah KSE. Fate of growth plate hypertrophic chondrocytes: death or lineage extension? Develop Growth Differ. 2015;57:179–92.

    Article  CAS  Google Scholar 

  11. Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 2014;10(12):e1004820.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ono N, Ono W, Nagasawa T, Kronenberg HM. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014;16(12):1157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jing Y, Zhou X, Han X, Jing J, von der Mark K, Wang J, et al. Chondrocytes directly transform into bone cells in mandibular condyle growth. J Dent Res. 2015;94(12):1668–75. https://doi.org/10.1177/0022034515598135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bahney CS, Hu DP, Taylor AJ, Ferro F, Britz HM, Hallgrimsson B, et al. Stem cell–derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res. 2014;29(5):1269–82. https://doi.org/10.1002/jbmr.2148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Houben A, Kostanova-Poliakova D, Weissenböck M, Graf J, Teufel S, von der Mark K, et al. β-Catenin activity in late hypertrophic chondrocytes locally orchestrates osteoblastogenesis and osteoclastogenesis. Development. 2016;143:3826–38. https://doi.org/10.1242/dev.137489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144:221–34. https://doi.org/10.1242/dev.130807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Park J, Gebhardt M, Golovchenko S, Perez-Branguli F, Hattori T, Hartmann C, et al. Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open. 2015;4:608–21. https://doi.org/10.1242/bio.201411031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Matsushita M, Kito H, Mishima K, Kadono I, Sugiura H, Hasegawa S, et al. Low bone mineral density in achondroplasia and hypochondroplasia. Pediatr Int. 2016;58:705–8.

    Article  CAS  PubMed  Google Scholar 

  19. Chung U-I, Lanske B, Lee K, Li E, Kronenberg HM. The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc Natl Acad Sci U S A. 1998;95:13030–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chagin AS, Vuppalapati KK, Kobayashi T, Guo J, Hirai T, Chen M, et al. G-protein stimulatory subunit alpha and Gq/11α G-proteins are both required to maintain quiescent stem-like chondrocytes. Nat Commun. 2014;5:3673. https://doi.org/10.1038/ncomms4673.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chung U-I, Schipani E, McMahon AP, Kronenberg HM. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest. 2001;107:295–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science. 1996;273:613–22.

    Article  CAS  PubMed  Google Scholar 

  23. Mak KK, Kronenberg HM, Chuang P-T, Mackem S, Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development. 2008;135:1947–56.

    Article  CAS  PubMed  Google Scholar 

  24. Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development. 2001;128:4523–34.

    CAS  PubMed  Google Scholar 

  25. Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell. 2002;3:439–49.

    Article  CAS  PubMed  Google Scholar 

  26. Witte F, Dokas J, Neuendorf F, Mundlos S, Stricker S. Comprehensive expression analysis of all Wnt genes and their major secreted antagonists during mouse limb development and cartilage differentiation. Gene Expr Patterns. 2009;9:215–23.

    Article  CAS  PubMed  Google Scholar 

  27. Andrade AC, Nilsson O, Barnes KM, Baron J. Wnt gene expression in the post-natal growth plate: regulation with chondrocyte differentiation. Bone. 2007;40:1361–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, et al. Developmental regulation of Wnt/β-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 2005;280(19):19185–95.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Y, Topol L, Lee H, Wu J. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development. 2003;130:1003–15.

    Article  CAS  PubMed  Google Scholar 

  30. Church V, Nohno T, Linker C, Marcelle C, Francis-West P. Wnt regulation of chondrocyte differentiation. J Cell Sci. 2002;115:4809–18.

    Article  CAS  PubMed  Google Scholar 

  31. Dao DY, Yang X, Flick LM, Chen D, Hilton MJ, O’Keefe RJ. Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res. 2010;28:89–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Serra R, Karaplis A, Sohn P. Parathyroid hormone–related peptide (PTHrP)-dependent and -independent effects of transforming growth factor β (TGF-β) on endochondral bone formation. J Cell Biol. 1999;145(4):783–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Butler AA, Le Roith D. Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol. 2001;63:141–64.

    Article  CAS  PubMed  Google Scholar 

  34. •• Uchimura T, Hollander JM, Nakamura DS, Liu Z, Rosen CJ, Georgakoudi I, et al. An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth. Development. 2017;144:3533–46. This study identifies a role for IGF2 in regulating glucose metabolism in growth plate chondrocytes and a role for glucose metabolism in controlling postnatal cartilage development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kiepe D, Ciarmatori S, Haarmann A, Tonshoff B. Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5. Am J Physiol Endocrinol Metab. 2006;290(2):E363–71. https://doi.org/10.1152/ajpendo.00363.2005.

    Article  CAS  PubMed  Google Scholar 

  36. Yakar S, Rosen CJ, Bouxsein ML, Sun H, Mejia W, Kawashima Y, et al. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J. 2009;23:709–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ueki M, Tanaka N, Tanimoto K, Nishio C, Honda C, Lin Y-Y, et al. The effect of mechanical loading on the metabolism of growth plate chondrocytes. Ann Biomed Eng. 2008;36(5):793–800.

    Article  PubMed  Google Scholar 

  38. Narváez-Tovar CA, Garzón-Alvarado DA. Computational modeling of the mechanical modulation of the growth plate by sustained loading. Theor Biol Med Model. 2012;9:41.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kozhemyakina E, Lassar AB, Zelzer E. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015;142(5):817–31. https://doi.org/10.1242/dev.105536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dashty M. A quick look at biochemistry: carbohydrate metabolism. Clin Biochem. 2013;46:1339–52.

    Article  CAS  PubMed  Google Scholar 

  41. Bartrons R, Caro J. Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr. 2007;39:223–9.

    Article  CAS  PubMed  Google Scholar 

  42. Iannotti JP. Growth plate physiology and pathology. Orthop Clin North Am. 1990;21(1):1–17.

    CAS  PubMed  Google Scholar 

  43. •• Ohara H, Tamayama T, Maemura K, Kanbara K, Hayasaki H, Abe M, et al. Immunocytochemical demonstration of glucose transporters in epiphyseal growth plate chondrocytes of young rats in correlation with autoradiographic distribution of 2-deoxyglucose in chondrocytes of mice. Acta Histochem. 2001;103:365–78. This study demonstrates the localization of glucose transporter proteins in the epiphyseal growth plate.

    Article  CAS  PubMed  Google Scholar 

  44. Mobasheri A, Vannucci SJ, Bondy CA, Carter SD, Innes JF, Arteaga MF, et al. Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis. Histol Histopathol. 2002;17:1239–67.

    CAS  PubMed  Google Scholar 

  45. Mobasheri A, Dobson H, Mason SL, Cullingham F, Shakibaei M, Moley JF, et al. Expression of the GLUT1 and GLUT9 facilitative glucose transporters in embryonic chondroblasts and mature chondrocytes in ovine articular cartilage. Cell Biol Int. 2005;29:249–60.

    Article  CAS  PubMed  Google Scholar 

  46. Uldry M, Ibberson M, Hosokawa M, Thorens B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 2002;524:199–203.

    Article  CAS  PubMed  Google Scholar 

  47. Colville CA, Seatter MJ, Jess TJ, Gould GW, Thomas HM. Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors. Biochem J. 1993;290:701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. • Maor G, Karnieli E. The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. Endocrinology. 1999;140(4):1841–51. This study shows regulation of long bone development by insulin signaling and regulation of GLUT4 in the growth plate by insulin.

    Article  CAS  PubMed  Google Scholar 

  49. •• Rajpurohit R, Mansfield K, Ohyama K, Ewert D, Shapiro IM. Chondrocyte death is linked to development of a mitochondrial membrane permeability transition in the growth plate. J Cell Physiol. 1999;179:287–96. This study demonstrates the differences among zones of the growth plate in the use of glycolysis and oxidative phosphorylation.

    Article  CAS  PubMed  Google Scholar 

  50. Karner CM, Long F. Glucose metabolism in bone. Bone. 2018;115:2–7.

    Article  CAS  PubMed  Google Scholar 

  51. Torres ES, Andrade CV, Fonesca EC, Mello MA, Duarte MEL. Insulin impairs the maturation of chondrocytes in vitro. Braz J Med Biol Res. 2003;36:1185–92.

    Article  CAS  PubMed  Google Scholar 

  52. Böhme K, Conscience-Egli M, Tschan T, Winterhalter KH, Bruckner P. Induction of proliferation or hypertrophy of chondrocytes in serum-free culture: the role of insulin-like growth factor-I, insulin, or thyroxine. J Cell Biol. 1992;116(4):1035–42.

    Article  PubMed  Google Scholar 

  53. Zhang F, He Q, Tsang WP, Garvey WT, Chan WY, Wan C. Insulin exerts direct, IGF-1 independent actions in growth plate chondrocytes. Bone Res. 2014;2:14012. https://doi.org/10.1038/boneres.2014.12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yakar S, Werner H, Rosen CJ. 40 years of IGF1: insulin-like growth factors: actions on the skeleton. J Mol Endocrinol. 2018;61(1):T115–T37.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. White MF, Copps KD. Chapter 33 - the mechanisms of insulin action. Seventh ed. Endocrinology: Adult and Pediatric. W.B. Saunders; 2016.

  56. • Wang J, Zhou J, Bondy CA. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J. 1999;13(14):1985–90. This study demonstrates the role of IGF1 in cartilage development and in regulation of GLUT4 and GSK3 in epiphyseal cartilage.

    Article  CAS  PubMed  Google Scholar 

  57. Esen E, Lee S-Y, Wice BM, Long F. PTH promotes bone anabolism by stimulating aerobic glycolysis via IGF signaling. J Bone Miner Res. 2015;30(11):1959–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bhaumick B, Bala RM. Differential effects of insulin-like growth factors I and II on growth, differentiation and glucoregulation in differentiating chondrocyte cells in culture. Acta Endocrinol. 1991;125:201–11.

    Article  CAS  PubMed  Google Scholar 

  59. Bhaumick B, Bala RM. Parallel effects of insulin-like growth factor-II and insulin on glucose metabolism of developing mouse embryonic limb buds in culture. Biochem Biophys Res Commun. 1988;152(1):359–67.

    Article  CAS  PubMed  Google Scholar 

  60. Eggenschwiler J, Ludwig T, Fisher P, Leighton PA, Tilghman SM, Efstratiadis A. Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith–Wiedemann and Simpson–Golabi–Behmel syndromes. Genes Dev. 1997;11:3128–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Louvi A, Accili D, Efstratiadis A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol. 1997;189:33–48.

    Article  CAS  PubMed  Google Scholar 

  62. Perdue JF, LeBon TR, Kato J, Hampton B, Fujita-Yamaguchi Y. Binding specificities and transducing function of the different molecular weight forms of insulin-like growth factor-II (IGF-II) on IGF-I receptors. Endocrinology. 1991;129(6):3101–8.

    Article  CAS  PubMed  Google Scholar 

  63. Pandini G, Medico E, Conte E, Sciacca L, Vigneri R, Belfiore A. Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. J Biol Chem. 2003;278(43):42178–89.

    Article  CAS  PubMed  Google Scholar 

  64. Zavorka ME, Connelly CM, Grosely R, MacDonald RG. Inhibition of insulin-like growth factor II (IGF-II)-dependent cell growth by multidentate pentamannosyl 6-phosphate-based ligands targeting the mannose 6-phosphate/IGF-II receptor. Oncotarget. 2016;7(38):62386–410.

    Article  PubMed  PubMed Central  Google Scholar 

  65. •• Lee S-Y, Abel ED, Long F. Glucose metabolism induced by Bmp signaling is essential for murine skeletal development. Nat Commun. 2018;9. https://doi.org/10.1038/s41467-018-07316-5. This study identifies a critical role for BMP signaling-regulated GLUT1 in proliferation and hypertrophy of chondrocytes during skeletal development.

  66. Watanabe H, Bohensky J, Freeman T, Srinivas V, Shapiro IM. Hypoxic induction of UCP3 in the growth plate: UCP3 suppresses chondrocyte autophagy. J Cell Physiol. 2008;216:419–25. https://doi.org/10.1002/jcp.21408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival. Genes Dev. 2001;15:2865–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Pfander D, Cramer T, Schipani E, Johnson RS. HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes. J Cell Sci. 2003;116(9):1819–26.

    Article  CAS  PubMed  Google Scholar 

  69. Hashimoto T, Murata Y, Urushihara Y, Shiga S, Takeda K, Hosoi Y. Severe hypoxia increases expression of ATM and DNA-PKcs and itincreases their activities through Src and AMPK signaling pathways. Biochem Biophys Res Commun. 2018;505:13–9.

    Article  CAS  PubMed  Google Scholar 

  70. Musi N, Goodyear LJ. AMP-activated protein kinase and muscle glucose uptake. Acta Physiol Scand. 2003;178:337–45.

    Article  CAS  PubMed  Google Scholar 

  71. Yang Y, Wang Y, Kong Y, Zhang X, Zhang H, Gang Y, et al. Mechanical stress protects against osteoarthritis via regulation of the AMPK/NF-κB signaling pathway. J Cell Physiol. 2018. https://doi.org/10.1002/jcp.27592.

  72. Chen L-Y, Wang Y, Terkeltaub R, Liu-Bryan R. Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function. Osteoarthr Cartil. 2018;26:1539–50.

    Article  PubMed  Google Scholar 

  73. Mickelson MN. Effect of uncoupling agents and respiratory inhibitors on the growth of Streptococcus agalactiae. J Bacteriol. 1974;120(2):733–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Brighton CT, Lackman RD, Cuckler JM. Absence of the glycerol phosphate shuttle in the various zones of the growth plate. J Bone Joint Surg. 1983;65-A(5):663–6.

    Article  CAS  Google Scholar 

  75. Houten SM, Wanders RJA. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J Inherit Metab Dis. 2010;33:469–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. • Dunham J, Dodds RA, Nahir AM, Frost GTB, Catterall A, Bitensky L, et al. Aerobic glycolysis of bone and cartilage: the possible involvement of fatty acid oxidation. Cell Biochem Funct. 1983;1:168–72. This study demonstrates the activities of key metabolic enzymes in glucose metabolism in different zones of the growth plate.

    Article  CAS  PubMed  Google Scholar 

  77. Kim J-W, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85. https://doi.org/10.1016/j.cmet.2006.02.002.

    Article  CAS  PubMed  Google Scholar 

  78. Mansfield K, Rajpurohit R, Shapiro IM. Extracellular phosphate ions cause apoptosis of terminally differentiated epiphyseal chondrocytes. J Cell Physiol. 1999;179:276–86.

    Article  CAS  PubMed  Google Scholar 

  79. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77:4–12.

    Article  CAS  PubMed  Google Scholar 

  80. Miedlich SU, Zalutskaya A, Zhu ED, Demay MB. Phosphate-induced apoptosis of hypertrophic chondrocytes is associated with a decrease in mitochondrial membrane potential and is dependent upon Erk1/2 phosphorylation. J Biol Chem. 2010;285(24):18270–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shapiro IM, Lee NH. The effect of oxygen, phosphoenolpyruvate and pH on the release of calcium from chondrocyte mitochondria. Metab Bone Dis Relat Res. 1978;1:173–7.

    Article  CAS  Google Scholar 

  82. Matthews JL, Martin JH, Sampson HW, Kunin AS, Roan JH. Mitochondrial granules in the normal and rachitic rat epiphysis. Calcif Tissue Res. 1970;5:91–9.

    Article  CAS  PubMed  Google Scholar 

  83. Lee RB, Urban JPG. Evidence for a negative Pasteur effect in articular cartilage. Biochem J. 1997;321:95–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee RB, Urban JPG. Functional replacement of oxygen by other oxidants in articular cartilage. Arthritis Rheum. 2002;46(12):3190–200.

    Article  CAS  PubMed  Google Scholar 

  85. Huang S, Heikal AA, Webb WW. Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein. Biophys J. 2002;82:2811–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kunz WS, Kunz W. Contribution of different enzymes to flavoprotein fluorescence of isolated rat liver mitochondria. Biochim Biophys Acta. 1985;841:237–46.

    Article  CAS  PubMed  Google Scholar 

  87. Heikal AA. Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies. Biomark Med. 2010;4(2):241–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Quinn KP, Sridharan GV, Hayden RS, Kaplan DL, Lee K, Georgakoudi I. Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation. Sci Rep. 2013;3:3432. https://doi.org/10.1038/srep03432.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Wang C, Silverman RM, Shen J, O’Keefe RJ. Distinct metabolic programs induced by TGF-β1 and BMP2 in human articular chondrocytes with osteoarthritis. J Orthop Translat. 2018;12:66–73.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Heywood HK, Knight MM, Lee DA. Both superficial and deep zone articular chondrocyte subpopulations exhibit the Crabtree effect but have different basal oxygen consumption rates. J Cell Physiol. 2010;223:630–9.

    CAS  PubMed  Google Scholar 

  91. Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013;17:745–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Karner CM, Esen E, Chen J, Hsu F-F, Turk J, Long F. Wnt protein signaling reduces nuclear acetyl-CoA levels to suppress gene expression during osteoblast differentiation. J Biol Chem. 2016;291(25):13028–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhao X, Petursson F, Viollet B, Lotz M, Terkeltaub R, Liu-Bryan R. Peroxisome proliferator-activated receptor γ coactivator 1α and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheum. 2014;66(11):3073–82.

    Article  CAS  Google Scholar 

  94. Chen L-Y, Lotz M, Terkeltaub R, Liu-Bryan R. Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. J Biol Chem. 2018;293(31):12259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stincone A, Prigione A, Cramer T, Wamelink MMC, Campbell K, Cheung E, et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc. 2015;90:927–63.

    Article  PubMed  Google Scholar 

  96. • Silverton SF, Matsumoto H, DeBolt K, Reginato A, Shapiro IM. Pentose phosphate shunt metabolism by cells of the chick growth cartilage. Bone. 1989;10:45–51. This study relates activity of the pentose phosphate pathway to oxygen utilization and NADPH production during chondrocyte maturation.

    Article  CAS  PubMed  Google Scholar 

  97. Hough S, Russell JE, Teitelbaum SL, Avioli LV. Regulation of epiphyseal cartilage metabolism and morphology in the chronic diabetic rat. Calcif Tissue Int. 1983;35:115–21.

    Article  CAS  PubMed  Google Scholar 

  98. Clancy RM, Abramson SB, Kohne C, Rediske J. Nitric oxide attenuates cellular hexose monophosphate shunt response to oxidants in articular chondrocytes and acts to promote oxidant injury. J Cell Physiol. 1997;172:183–91.

    Article  CAS  PubMed  Google Scholar 

  99. Adeva-Andany MM, González-Lucán M, Donapetry-García C, Fernández-Fernández C, Ameneiros-Rodríguez E. Glycogen metabolism in humans. BBA Clin. 2016;5:85–100.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012;441:763–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fang X, Yu SX, Lu Y, Bast RCJ, Woodgett JR, Mills GB. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A. 2000;97(22):11960–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tokunaga H, Watanabe J, Kanai K, Sakaida M, Kanamura S. Glucose 6-phosphatase and glycogen phosphorylase activities in chondrocytes in epiphyseal cartilage of growing rats. Anat Rec. 1987;219:356–62.

    Article  CAS  PubMed  Google Scholar 

  103. Daimon T. The presence and distribution of glycogen particles in chondrogenic cells of the tibiotarsal anlage of developing chick embryos. Calcif Tissue Res. 1977;23:45–51.

    Article  CAS  PubMed  Google Scholar 

  104. Godman GC, Porter KR. Chondrogenesis, studied with the electron microscope. J Biophys Biochem Cytol. 1960;8:719–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Marchand F. Ueber eine Geschwulst aus quergestreiften Muskelfasern mit ungewöhnlichem Gehalte an Glykogen, nebst Bemerkungen über das Glykogen in einigen fötalen Geweben. Virchows Arch Pathol Anat Physiol Klin Med. 1885;100(1):42–65.

    Article  Google Scholar 

  106. Hutchison MR, Bassett MH, White PC. Insulin-like growth factor-I and fibroblast growth factor, but not growth hormone, affect growth plate chondrocyte proliferation. Endocrinology. 2007;148(7):3122–30.

    Article  CAS  PubMed  Google Scholar 

  107. Gillespie JR, Ulici V, Dupuis H, Higgs A, DiMattia A, Patel SC, et al. Deletion of glycogen synthase kinase-3β. Endocrinology. 2011;152(5):1755–66.

    Article  CAS  PubMed  Google Scholar 

  108. Long F, Joeng KS, Xuan S, Efstratiadis A, McMahon AP. Independent regulation of skeletal growth by Ihh and IGF signaling. Dev Biol. 2006;298:327–33.

    Article  CAS  PubMed  Google Scholar 

  109. Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2009;35(3):161–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Edouard T, Grünenwald S, Gennero I, Salles JP, Tauber M. Prevalence of IGF1 deficiency in prepubertal children with isolated short stature. Eur J Endocrinol. 2009;161:43–50.

    Article  CAS  PubMed  Google Scholar 

  111. Kamboj M. Short stature and growth hormone. Indian J Pediatr. 2005;72(2):149–57.

    Article  PubMed  Google Scholar 

  112. Iliev DI, Kannenberg K, Weber K, Binder G. IGF-I sensitivity in silver-Russell syndrome with IGF2/H19 hypomethylation. Growth Hormon IGF Res. 2014;24:187–91.

    Article  CAS  Google Scholar 

  113. Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Büttel H-M, et al. Paternally inherited IGF2 mutation and growth restriction. N Engl J Med. 2015;373:349–56.

    Article  CAS  PubMed  Google Scholar 

  114. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2010;18:8–14.

    Article  PubMed  Google Scholar 

  115. Sparago A, Cerrato F, Vernucci M, Battista Ferrero G, Cirillo Silengo M, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet. 2004;36(9):958–60.

    Article  CAS  PubMed  Google Scholar 

  116. Ornitz DM. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev. 2005;16:205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wong SC, Dobie R, Altowati MA, Werther GA, Farquharson C, Ahmed SF. Growth and the growth hormone-insulin like growth factor 1 axis in children with chronic inflammation: current evidence, gaps in knowledge, and future directions. Endocr Rev. 2016;37(1):62–110.

    Article  CAS  PubMed  Google Scholar 

  118. Liem JJ, Rosenberg AM. Growth patterns in juvenile rheumatoid arthritis. Clin Exp Rheumatol. 2003;21:663–8.

    CAS  PubMed  Google Scholar 

  119. Zhang Z, Lindstrom MJ, Lai HJ. Pubertal height velocity and associations with prepubertal and adult heights in cystic fibrosis. J Pediatr. 2013;163(2):376–82.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Carpio LR, Bradley EW, McGee-Lawrence ME, Weivoda MM, Poston DD, Dudakovic A, et al. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci Signal. 2016;9(440):ra79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J Immunol. 2001;167:7001–8.

    Article  CAS  PubMed  Google Scholar 

  122. Mårtensson K, Chrysis D, Sävendahl L. Interleukin-1β and TNF-α act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res. 2004;19(11):1805–12.

    Article  CAS  PubMed  Google Scholar 

  123. Kiely A, McClenaghan NH, Flatt PR, Newsholme P. Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic β-cell line. J Endocrinol. 2007;195:113–23.

    Article  CAS  PubMed  Google Scholar 

  124. Chen L, Chen R, Wang H, Liang F. Mechanisms linking inflammation to insulin resistance. Int J Endocrinol. 2015;2015:508409.

    PubMed  PubMed Central  Google Scholar 

  125. Su N, Jin M, Chen L. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003. https://doi.org/10.1038/boneres.2014.3.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Munns CFJ, Batch JA. Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed. 2001;84:F67–F9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

    Judith M. Hollander & Li Zeng

  2. Program of Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

    Li Zeng

  3. Program of Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

    Li Zeng

  4. Department of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA

    Li Zeng

  5. Department of Orthopaedics, Tufts Medical Center, Boston, MA, 02111, USA

    Li Zeng

Authors
  1. Judith M. Hollander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Zeng.

Ethics declarations

Conflict of Interest

Judith M. Hollander and Li Zeng declare that they have no conflict of interest.

Human and Animal Rights

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Skeletal Development

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hollander, J.M., Zeng, L. The Emerging Role of Glucose Metabolism in Cartilage Development. Curr Osteoporos Rep 17, 59–69 (2019). https://doi.org/10.1007/s11914-019-00506-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-019-00506-0

Keywords

Search

Navigation