Abstract
Growth plate chondrocytes are responsible for bone growth through proliferation and differentiation. However, the way they experience physiological loads and regulate bone formation, especially during the later developmental phase in the mature growth plate, is still under active investigation. In this study, a previously developed multiscale finite element model of the growth plate is utilized to study the stress and strain distributions within the cartilage at the cellular level when rapidly compressed to 20 %. Detailed structures of the chondron are included in the model to examine the hypothesis that the same combination of mechanoregulatory signals shown to maintain cartilage or stimulate osteogenesis or fibrogenesis in the cartilage anlage or fracture callus also performs the same function at the cell level within the chondrons of growth plate cartilage. Our cell-level results are qualitatively and quantitatively in agreement with tissue-level theories when both hydrostatic cellular stress and strain are considered simultaneously in a mechanoregulatory phase diagram similar to that proposed at the tissue level by Claes and Heigele for fracture healing. Chondrocytes near the reserve/proliferative zone border are subjected to combinations of high compressive hydrostatic stresses (\(-0.4\) MPa), and cell height and width strains of \(-12\) to \(+9\,\%\) respectively, that maintain cartilage and keep chondrocytes from differentiating and provide conditions favorable for cell division, whereas chondrocytes closer to the hypertrophic/calcified zone undergo combinations of lower compressive hydrostatic stress (\(-0.18\) MPa) and cell height and width strains as low as \(-4\) to +4 %, respectively, that promote cell differentiation toward osteogenesis; cells near the outer periphery of the growth plate structure experience a combination of low compressive hydrostatic stress (0 to \(-0.15\) MPa) and high maximum principal strain (20–29 %) that stimulate cell differentiation toward fibrocartilage or fibrous tissue.
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References
Allen DM, Mao JJ (2004) Heterogeneous nanostructural and nanoelastic properties of pericellular and interterritorial matrices of chondrocytes by atomic force microscopy. J Struct Biol 145(3):196–204
Amini S, Veilleux D, Villemure I (2010) Tissue and cellular morphological changes in growth plate explants under compression. J Biomech 43(13):2582–2588
Appelman TP, Mizrahi J, Seliktar D (2011) A finite element model of cell-matrix interactions to study the differential effect of scaffold composition on chondrogenic response to mechanical stimulation. J Biomech Eng 133(4):041010
Armstrong CG, Lai WM, Mow VC (1984) An analysis of the unconfined compression of articular cartilage. J Biomech Eng 106(2):165–173
Ateshian GA, Lai WM, Zhu WB, Mow VC (1994) An asymptotic solution for the contact of two biphasic cartilage layers. J Biomech 27(11):1347–1360
Bergmann G, Bender A, Graichen F, Dymke J, Rohlmann A, Trepczynski A, Heller MO, Kutzner I (2014) Standardized loads acting in knee implants. PLoS One 9(1):e86035
Bleuel J, Zaucke F, Brüggemann GP, Niehoff A (2015) Effects of cyclic tensile strain on chondrocyte metabolism: a systematic review. PloS One 10(3):e0119816
Bonnel F, Peruchon E, Baldet P, Dimeglio A, Rabischong P (1983) Effects of compression on growth plates in the rabbit. Acta Orthop Scand 54:730–733
Brown TD, Singerman RJ (1986) Experimental determination of the linear biphasic constitutive coefficients of human fetal proximal femoral chondroepiphysis. J Biomech 19(8):597–605
Burridge K, Fath K, Kelly T, Nuckolls G, Turner C (1988) Focal adhesions: transmembrane junctions between the extracellular-matrix and the cytoskeleton. Ann Rev Cell Biol 4:487–525
Bylski-Austrow DI, Wall EJ, Rupert MP, Roy DR, Crawford AH (2001) Growth plate forces in the adolescent human knee: a radiographic and mechanical study of epiphyseal staples. J Pediatr Orthop 21:817–823
Carter DR, Wong M (1988a) The role of mechanical loading histories in the development of diarthrodial joints. J Orthop Res 6(6):804–816
Carter DR, Wong M (1988b) Mechanical stresses and endochondral ossification in the chondroepiphysis. J Orthop Res 6:148–154
Carter DR, Wong M (1990) Mechanical stresses in joint morphogenesis and maintenance. In: Mow VC, Ratcliffe A, Woo SL-Y (eds) Biomechanics of diarthrodial joints, vol 2. Springer, New York, pp 155–174
Carter DR, Orr TE (1992) Skeletal development and bone functional adaptation. J Bone Miner Res 7:389–395
Carter DR, Beaupré GS (1999) Linear elastic and poroelastic models of cartilage can produce comparable stress results: a comment on Tanck et al. (J Biomech 32: 153-161, 1999). J Biomech 32(11):1255-7
Carter DR, Wong M (2003) Modelling cartilage mechanobiology. Philos Trans R Soc Lond Ser B-Biol Sci 358(1437):1461–1471
Carter DR, Orr TE, Fyhrie DP, Schurman DJ (1987) Influences of mechanical stress on prenatal and postnatal skeletal development. Clin Orthop Relat Res 219:237–250
Carter DG, Blenman PR, Beaupré GS (1988) Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J Orthop Res 6:736–748
Carter DR, Beaupré GS, Giori NJ, Helms JA (1998) Mechanobiology of skeletal regeneration. Clin Orthop Relat Res 355:S41–S55
Chahine NO, Hung CT, Ateshian GA (2007) In-situ measurements of chondrocyte deformation under transient loading. Eur Cells Mater 13:100–111
Chan DD, Cai L, Butz KD, Trippel SB, Nauman EA, Neu CP (2016) In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee. Sci Rep 6:19220. doi:10.1038/srep19220
Claes LE, Heigele CA (1999) Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 32(3):255–266
Darling EM, Topel M, Zauscher S, Vail TP, Guilak F (2008) Viscoelastic properties of human mesenchymally-derived stem cells and primary osteoblasts, chondrocytes, and adipocytes. J Biomech 41(2):454–464
Farnum CE, Wilsman NJ (2011) Orientation of primary cilia of articular chondrocytes in three-dimensional space. Anat Rec 294(3):533–549
Ferguson C, Alpern E, Miclau T, Helms JA (1999) Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev 87(1):57–66
Frost HM (1990) Skeletal structural adaptations to mechanical usage (SATMU): 3—the hyaline cartilage modeling problem. Anat Rec 226(4):423–432
Frost HM (1997) Defining osteopenias and osteoporoses: another view (with insights from a new paradigm). Bone 20(5):385–391
Gao J, Williams JL, Roan E (2014) On the state of stress in the growth plate under physiologic compressive loading. Open J Biophys 4(1):13–21. doi:10.4236/ojbiphy.2014.41003
Gao J, Roan E, Williams JL (2015) Regional variations in growth plate chondrocyte deformation as predicted by three-dimensional multi-scale simulations. PLoS ONE 10(4):e0124862. doi:10.1371/journal.pone.0124862
Guilak F, Mow VC (2000) The mechanical environment of the chondrocyte: a biphasic finite element model of cell–matrix interactions in articular cartilage. J Biomech 33(12):1663–1673
Haycraft CJ, Serra R (2008) Cilia involvement in patterning and maintenance of the skeleton. Curr Top Dev Biol 85:303–332
Hert J (1976) Growth of the epiphyseal plate in circumference. Acta Anat 82:420–436
Higginson GR, Litchfield MR, Snaith J (1976) Load-displacement-time characteristics of articular cartilage. Int J Mech Sci 18(9):481–486
Hosseini A, Van de Velde SK, Kozanek M, Gill TJ, Grodzinsky AJ, Rubash HE, Li G (2010) In-vivo time-dependent articular cartilage contact behavior of the tibiofemoral joint. Osteoarthr Cartil 18(7):909–916
Hueter C (1863) Anatomische Studien an den Extremitätengelenken Neugeborener und Erwachsener. Virchows Archiv 26(5):484–519
Jensen CG, Poole CA, McGlashan SR, Marko M, Issa ZI, Vujcich KV, Bowser SS (2004) Ultrastructural, tomographic and confocal imaging of the chondrocyte primary cilium in situ. Cell Biol Int 28(2):101–110
Katta J, Jin Z, Ingham E, Fisher J (2009) Effect of nominal stress on the long term friction, deformation and wear of native and glycosaminoglycan deficient articular cartilage. Osteoarthr Cartil 17(5):662–668
Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937):332–336
Lai VK, Hadi MF, Tranquillo RT, Barocas VH (2013) A multiscale approach to modeling the passive mechanical contribution of cells in tissues. J Biomech Eng 135(7):071007
Leipzig ND, Athanasiou KA (2005) Unconfined creep compression of chondrocytes. J Biomech 38(1):77–85
Lerner AL, Kuhn JL (1997) Characterization of regional and age-related variations in the growth of the rabbit distal femur. J Orthop Res 15(3):353–361
Lerner AL, Kuhn JL, Hollister SJ (1998) Are regional variations in bone growth related to mechanical stress and strain parameters? J Biomech 31(4):327–335
Loboa EG, Wren TAL, Beaupré GS, Carter DR (2003) Mechanobiology of soft skeletal tissue differentiation: a computational approach of a fiber-reinforced poroelastic model based on homogeneous and isotropic simplifications. Biomech Model Mechanobiol 2(2):83–96
Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M (2008) Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol 40(1):46–62
Mann RA, Hagy J (1980) Biomechanics of walking, running, and sprinting. Am J Sports Med 8(5):345–350
Mao JJ, Nah HD (2004) Growth and development: hereditary and mechanical modulations. Am J Orthod Dentofac Orthop 125(6):676–689
Ng L, Hung H-H, Sprunt A, Chubinskaya S, Ortiz C, Grodzinsky A (2007) Nanomechanical properties of individual chondrocytes and their developing growth factor-stimulated pericellular matrix. J Biomech 40(5):1011–1023
Pauwels F (1960) Eine neue Theorie über den Einfluß mechanischer Reize auf die Differenzierung der Stützgewebe. Z Anat Entwicklung 121(6):478–515
Pauwels F (1965) Grundri\({\upbeta }\) einer Biomechanik der Frakturheilung: Gesammelte Abhandlungen zur funktionellen Anatomie des Bewegungsapparates. Springer, Berlin
Pauwels F (1980) Biomechanics of the locomotor apparatus. Springer, New York
Piszczatowski S (2011) Material aspects of growth plate modelling using Carter’s and tokes’s approaches. Acta Bioeng Biomech 13(3):3–14
Radhakrishnan P, Lewis NT, Mao JJ (2004) Zone-specific micromechanical properties of the extracellular matrices of growth plate cartilage. Ann Biomed Eng 32(2):284–291
Sachs F (1991) Mechanical transduction by membrane ion channels: a mini review. Mol Cell Biochem 104(1–2):57–60
Safran MR, Eckardt JJ, Kabo JM, Oppenheim WL (1992) Continued growth of the proximal part of the tibia after prosthetic reconstruction of the skeletally immature knee: estimation of the minimum growth force in vivo in humans. J Bone Joint Surg Am 74(8):1172–1179
Seeger-Nukpezah T, Golemis EA (2012) The extracellular matrix and ciliary signaling. Curr Opin Cell Biol 24(5):652–661
Shao YY, Wang L, Welter JF, Ballock RT (2012) Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone 50(1):79–84
Shapiro F, Holtrop ME, Glimcher MJ (1977) Organization and cellular biology of the perichondrial ossification groove of Ranvier. J Bone Joint Surg 59–A:703–723
Solomon L (1966) Diametric growth of the epiphysial plate. J Bone Joint Surg Br 48(1):170–177
Stokes IAF (2002) Mechanical effects on skeletal growth. J Musculoskelet Neuronal Interact 2(3):277–280
Stokes IAF, Clarck KC, Farnum CE, Aronsson DD (2007) Alterations in the growth plate associated with growth modulation by sustained compression or distraction. Bone 41:197–205
Stokes IAF, Aronsson DD, Dimock AN, Cortright V, Beck S (2006) Endochondral growth in growth plates of three species at two anatomical locations modulated by mechanical compression and tension. J Orthop Res 24:1327–1334
Temiyasathit S, Jacobs CR (2010) Osteocyte primary cilium and its role in bone mechanotransduction. Ann N Y Acad Sci 1192(1):422–428
Tutorino JC, Khubchandani ZG, Williams JL, Cobb CM, Schmidt TL (2001) Can the epiphyseal growth plate be injured in compression?. In: Transactions of the 47th annual meeting of the orthopaedic research society, vol 26, p 353
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 30;49(5):996–1004
Villemure I, Stokes IAF (2009) Growth plate mechanics and mechanobiology: a survey of present understanding. J Biomech 42(12):1793–1803
Vinardell T, Rolfe RA, Buckley CT, Meyer EG, Ahearne M, Murphy P, Kelly DJ (2012) Hydrostatic pressure acts to stabilise a chondrogenic phenotype in porcine joint tissue derived stem cells. Eur Cells Mater 23:121–134
Volkmann R (1862) Verletzungen und Krankenheiten der Bewegungsorgane. In: von Pitha FR, Billroth T (eds) Handbuch der allgemeinen und speciellen Chirurgie Bd II Teil II. Ferdinand Enke, Stuttgart
Watson PA (1991) Function follows form: feneration of intracellular signal by cell-deformation. FASEB J 5(7):2013–2019
Winyard P, Jenkins D (2011) Putative roles of cilia in polycystic kidney disease. Biochim Biophys Acta (BBA)-Mol Basis Dis 1812(10):1256–1262
Wong M, Carter DR (1990) A theoretical model of endochondral ossification and bone architectural construction in long bone ontogeny. Anat Embryol 181:523–532
Wong M, Siegrist M, Goodwin K (2003) Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes. Bone 33(4):685–693
Wosu R, Sergerie K, Lévesque M, Villemure I (2012) Mechanical properties of the porcine growth plate vary with developmental stage. Biomech Model Mechanobiol 1;11(3–4):303–312
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Gao, J., Williams, J.L. & Roan, E. Multiscale modeling of growth plate cartilage mechanobiology. Biomech Model Mechanobiol 16, 667–679 (2017). https://doi.org/10.1007/s10237-016-0844-8
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DOI: https://doi.org/10.1007/s10237-016-0844-8