Skip to main content
Log in

Mechanical Stimulation of Growth Plate Chondrocytes: Previous Approaches and Future Directions

  • Published:
Experimental Mechanics Aims and scope Submit manuscript

Abstract

Growth plate cartilage resides near the ends of long bones and is the primary driver of skeletal growth. During growth, both intrinsically and extrinsically generated mechanical stresses act on chondrocytes in the growth plate. Although the role of mechanical stresses in promoting tissue growth and homeostasis has been strongly demonstrated in articular cartilage of the major skeletal joints, effects of stresses on growth plate cartilage and bone growth are not well established. Here, we review the literature on mechanobiology in growth plate cartilage at macroscopic and microscopic scales, with particular emphasis on comparison of results obtained using different methodological approaches, as well as from whole animal and in vitro experiments. To answer these questions, macroscopic mechanical stimulators have been developed and applied to study mechanobiology of growth plate cartilage and chondrocytes. However, the previous approaches have tested a limited number of stress conditions, and the mechanobiology of a single chondrocyte has not been well studied due to limitations of the macroscopic mechanical stimulators. We explore how microfluidics devices can overcome these limitations and improve current understanding of growth plate chondrocyte mechanobiology. In particular, microfluidic devices can generate multiple stress conditions in a single platform and enable real-time monitoring of metabolism and cellular behavior using optical microscopy. Systematic characterization of the chondrocytes using microfluidics will enhance our understanding of how to use mechanical stresses to control the bone growth and the properties of tissue-engineered growth plate cartilage.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937):332

    Google Scholar 

  2. DeLise AM, Fischer L, Tuan RS (2000) Cellular interactions and signaling in cartilage development. Osteoarthr Cartil 8(5):309–334

    Google Scholar 

  3. Roselló-Díez A, Joyner AL (2015) Regulation of long bone growth in vertebrates; it is time to catch up. Endocr Rev 36(6):646–680

    Google Scholar 

  4. Hall BK, Miyake T (2000) All for one and one for all: condensations and the initiation of skeletal development. Bioessays 22(2):138–147

    Google Scholar 

  5. Yılmaz G (2016) Growth Plate. In: Musculoskeletal Research and Basic Science. Springer, Cham, pp 357–366

    Google Scholar 

  6. Villemure I, Stokes IAF (2009) Growth plate mechanics and mechanobiology. A survey of present understanding. J Biomech 42(12):1793–1803

    Google Scholar 

  7. Romereim SM, Dudley AT (2011) Cell polarity. Organogenesis 7(3):217–228

    Google Scholar 

  8. Romereim SM, Conoan NH, Chen B, Dudley AT (2014) A dynamic cell adhesion surface regulates tissue architecture in growth plate cartilage. Development 141(10):2085–2095

    Google Scholar 

  9. Kozhemyakina E, Lassar AB, Zelzer E (2015) A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development 142(5):817–831

    Google Scholar 

  10. Mak KK, Kronenberg HM, Chuang P-T, Mackem S, Yang Y (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135(11):1947–1956

    Google Scholar 

  11. Gao B, Song H, Bishop K, Elliot G, Garrett L, English MA, Andre P, Robinson J, Sood R, Minami Y, Economides AN, Yang Y (2011) Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev Cell 20(2):163–176

    Google Scholar 

  12. Killion CH, Mitchell EH, Duke CG, Serra R (2017) Mechanical loading regulates organization of the actin cytoskeleton and column formation in postnatal growth plate. Mol Biol Cell 28(14):1862–1870

    Google Scholar 

  13. Stokes IA, Mente PL, Iatridis JC, Farnum CE, Aronsson DD (2002) Enlargement of growth plate chondrocytes modulated by sustained mechanical loading. J Bone Joint Surg Am 84(10):1842–1848

    Google Scholar 

  14. Reich A, Jaffe N, Tong A, Lavelin I, Genina O, Pines M, Sklan D, Nussinovitch A, Monsonego-Ornan E (2005) Weight loading young chicks inhibits bone elongation and promotes growth plate ossification and vascularization. J Appl Physiol 98(6):2381–2389

    Google Scholar 

  15. Rodríguez JI, Palacios J, García-Alix A, Pastor I, Paniagua R (1988) Effects of immobilization on fetal bone development. A morphometric study in newborns with congenital neuromuscular diseases with intrauterine onset. Calcif Tissue Int 43(6):335–339

    Google Scholar 

  16. Cancel M, Grimard G, Thuillard-Crisinel D, Moldovan F, Villemure I (2009) Effects of in vivo static compressive loading on aggrecan and type II and X collagens in the rat growth plate extracellular matrix. Bone 44(2):306–315

    Google Scholar 

  17. Valteau B, Grimard G, Londono I, Moldovan F, Villemure I (2011) In vivo dynamic bone growth modulation is less detrimental but as effective as static growth modulation. Bone 49(5):996–1004

    Google Scholar 

  18. Walsh AJL, Lotz JC (2004) Biological response of the intervertebral disc to dynamic loading. J Biomech 37(3):329–337

    Google Scholar 

  19. Amini S, Veilleux D, Villemure I (2010) Tissue and cellular morphological changes in growth plate explants under compression. J Biomech 43(13):2582–2588

    Google Scholar 

  20. Sergerie K, Parent S, Beauchemin P-F, Londoño I, Moldovan F, Villemure I (2011) Growth plate explants respond differently to in vitro static and dynamic loadings. J Orthop Res 29(4):473–480

    Google Scholar 

  21. Bougault C, Paumier A, Aubert-Foucher E, Mallein-Gerin F (2008) Molecular analysis of chondrocytes cultured in agarose in response to dynamic compression. BMC Biotechnol 8(1):71

    Google Scholar 

  22. Zimmermann EA, Bouguerra S, Londoño I, Moldovan F, Aubin C-É, Villemure I (2017) In situ deformation of growth plate chondrocytes in stress-controlled static vs dynamic compression. J Biomech 56:76–82

    Google Scholar 

  23. Guilak F (1995) Compression-induced changes in the shape and volume of the chondrocyte nucleus. J Biomech 28(12):1529–1541

    Google Scholar 

  24. Knight MM, Ghori SA, Lee DA, Bader DL (1998) Measurement of the deformation of isolated chondrocytes in agarose subjected to cyclic compression. Med Eng Phys 20(9):684–688

    Google Scholar 

  25. Kaviani R, Londono I, Parent S, Moldovan F, Villemure I (2015) Compressive mechanical modulation alters the viability of growth plate chondrocytes in vitro. J Orthop Res 33(11):1587–1593

    Google Scholar 

  26. Ueki M, Tanaka N, Tanimoto K, Nishio C, Honda K, Lin Y-Y, Tanne Y, Ohkuma S, Kamiya T, Tanaka E, Tanne K (2008) The effect of mechanical loading on the metabolism of growth plate chondrocytes. Ann Biomed Eng 36(5):793–800

    Google Scholar 

  27. Sun K, Liu F, Wang J, Guo Z, Ji Z, Yao M (2017) The effect of mechanical stretch stress on the differentiation and apoptosis of human growth plate chondrocytes. In Vitro Cell Dev Biol-Animal 53(2):141–148

    Google Scholar 

  28. Liu Q, Hu X, Zhang X, Duan X, Yang P, Zhao F, Ao Y (2016) Effects of mechanical stress on chondrocyte phenotype and chondrocyte extracellular matrix expression. Sci Rep 6:37268

    Google Scholar 

  29. Draper ERC, Goodship AE (2003) A novel technique for four-point bending of small bone samples with semi-automatic analysis. J Biomech 36(10):1497–1502

    Google Scholar 

  30. Alberty A, Peltonen J, Ritsilä V (1993) Effects of distraction and compression on proliferation of growth plate chondrocytes: a study in rabbits. Acta Orthop Scand 64(4):449–455

    Google Scholar 

  31. Robling AG, Duijvelaar KM, Geevers JV, Ohashi N, Turner CH (2001) Modulation of appositional and longitudinal bone growth in the rat ulna by applied static and dynamic force. Bone 29(2):105–113

    Google Scholar 

  32. Wang X, Mao JJ (2002) Accelerated chondrogenesis of the rabbit cranial base growth plate by oscillatory mechanical stimuli. J Bone Miner Res 17(10):1843–1850

    Google Scholar 

  33. Akyuz E, Braun JT, Brown NAT, Bachus KN (2006) Static versus dynamic loading in the mechanical modulation of vertebral growth. Spine 31(25):E952–E958

    Google Scholar 

  34. Stokes IAF, Clark KC, Farnum CE, Aronsson DD (2007) Alterations in the growth plate associated with growth modulation by sustained compression or distraction. Bone 41(2):197–205

    Google Scholar 

  35. Ménard A-L, Grimard G, Valteau B, Londono I, Moldovan F, Villemure I (2014) In vivo dynamic loading reduces bone growth without histomorphometric changes of the growth plate. J Orthop Res 32(9):1129–1136

    Google Scholar 

  36. Aronsson DD, Stokes IAF, Rosovsky J, Spence H (1999) Mechanical modulation of calf tail vertebral growth: implications for scoliosis progression. Clin Spine Surg 12(2):141–146

    Google Scholar 

  37. Wang G, Woods A, Sabari S, Pagnotta L, Stanton L-A, Beier F (2004) RhoA/ROCK signaling suppresses hypertrophic chondrocyte differentiation. J Biol Chem 279(13):13205–13214

    Google Scholar 

  38. Delise AM, Tuan RS (2002) Analysis of N-cadherin function in limb mesenchymal chondrogenesis in vitro. Dev Dyn 225(2):195–204

    Google Scholar 

  39. Moraes C, Chen J-H, Sun Y, Simmons CA (2010) Microfabricated arrays for high-throughput screening of cellular response to cyclic substrate deformation. Lab Chip 10(2):227–234

    Google Scholar 

  40. Hosmane S, Fournier A, Wright R, Rajbhandari L, Siddique R, Yang IH, Ramesh KT, Venkatesan A, Thakor N (2011) Valve-based microfluidic compression platform: single axon injury and regrowth. Lab Chip 11(22):3888–3895

    Google Scholar 

  41. Young EWK, Wheeler AR, Simmons CA (2007) Matrix-dependent adhesion of vascular and valvular endothelial cells in microfluidic channels. Lab Chip 7(12):1759–1766

    Google Scholar 

  42. Byfield FJ, Wen Q, Levental I, Nordstrom K, Arratia PE, Miller RT, Janmey PA (2009) Absence of filamin a prevents cells from responding to stiffness gradients on gels coated with collagen but not fibronectin. Biophys J 96(12):5095–5102

    Google Scholar 

  43. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328(5986):1662–1668

    Google Scholar 

  44. Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21(12):745–754

    Google Scholar 

  45. Moraes C, Mehta G, Lesher-Perez SC, Takayama S (2012) Organs-on-a-chip: a focus on compartmentalized microdevices. Ann Biomed Eng 40(6):1211–1227

    Google Scholar 

  46. Huh D, Kim HJ, Fraser JP, Shea DE, Khan M, Bahinski A, Hamilton GA, Ingber DE (2013) Microfabrication of human organs-on-chips. Nat Protocols 8(11):2135–2157

    Google Scholar 

  47. Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotech 32(8):760–772

    Google Scholar 

  48. Lee JS, Romero R, Han YM, Kim HC, Kim CJ, Hong J-S, Huh D (2016) Placenta-on-a-chip: a novel platform to study the biology of the human placenta. J Matern Fetal Neonatal Med 29(7):1046–1054

    Google Scholar 

  49. Moraes C, Wang G, Sun Y, Simmons CA (2010) A microfabricated platform for high-throughput unconfined compression of micropatterned biomaterial arrays. Biomaterials 31(3):577–584

    Google Scholar 

  50. Moraes C, Zhao R, Likhitpanichkul M, Simmons CA, Sun Y (2011) Semi-confined compression of microfabricated polymerized biomaterial constructs. J Micromech Microeng 21(5):054014

    Google Scholar 

  51. Birukov KG, Birukova AA, Dudek SM, Verin AD, Crow MT, Zhan X, DePaola N, Garcia JGN (2002) Shear stress-mediated cytoskeletal remodeling and cortactin translocation in pulmonary endothelial cells. Am J Respir Cell Mol Biol 26(4):453–464

    Google Scholar 

  52. Wojciak-Stothard B, Ridley AJ (2003) Shear stress–induced endothelial cell polarization is mediated by rho and Rac but not Cdc42 or PI 3-kinases. J Cell Biol 161(2):429–439

    Google Scholar 

  53. Lu H, Koo LY, Wang WM, Lauffenburger DA, Griffith LG, Jensen KF (2004) Microfluidic shear devices for quantitative analysis of cell adhesion. Anal Chem 76(18):5257–5264

    Google Scholar 

Download references

Acknowledgements

This study was supported by Bioengineering for Human Health grant from the University of Nebraska-Lincoln (UNL) and the University of Nebraska Medical Centre (UNMC), and grant AR070242 from the NIH/NIAMS.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to A. T. Dudley or S. Ryu.

Ethics declarations

Conflict of Interest

The authors declare no competing financial interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, D., Erickson, A., Dudley, A.T. et al. Mechanical Stimulation of Growth Plate Chondrocytes: Previous Approaches and Future Directions. Exp Mech 59, 1261–1274 (2019). https://doi.org/10.1007/s11340-018-0424-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11340-018-0424-1

Keywords

Navigation