Mechanical regulation of chondrogenesis

Stem Cell Research & Therapy

Farshid Guilak²  Natasha Case¹  Christopher J O’Conor² 

[1] Department of Orthopaedic Surgery, Duke University Medical Center, 375 MSRB Box 3093, Durham, NC 27710, USA;Department of Biomedical Engineering, University of North Carolina – Chapel Hill, Chapel Hill, NC 27599, USA

关键词: Mechanical signal transduction;    Ion channel;    Synovial joint;    Regeneration;    Adipose stem cell;    Mesenchymal stem cell;    Tissue engineering;    Scaffold;    Cartilage defect;    Osteoarthritis;   

Others  :  1147674
DOI  :  10.1186/scrt211

【 摘 要 】

Mechanical factors play a crucial role in the development of articular cartilage in vivo. In this regard, tissue engineers have sought to leverage native mechanotransduction pathways to enhance in vitro stem cell-based cartilage repair strategies. However, a thorough understanding of how individual mechanical factors influence stem cell fate is needed to predictably and effectively utilize this strategy of mechanically-induced chondrogenesis. This article summarizes some of the latest findings on mechanically stimulated chondrogenesis, highlighting several new areas of interest, such as the effects of mechanical stimulation on matrix maintenance and terminal differentiation, as well as the use of multifactorial bioreactors. Additionally, the roles of individual biophysical factors, such as hydrostatic or osmotic pressure, are examined in light of their potential to induce mesenchymal stem cell chondrogenesis. An improved understanding of biomechanically-driven tissue development and maturation of stem cell-based cartilage replacements will hopefully lead to the development of cell-based therapies for cartilage degeneration and disease.

【 授权许可】

   
2013 BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Estes BT, Gimble JM, Guilak F: Mechanical signals as regulators of stem cell fate. Curr Top Dev Biol 2004, 60:91-126.
• [2]Aaron RK, Ciombor DM, Wang S, Simon B: Clinical biophysics: the promotion of skeletal repair by physical forces. Ann N Y Acad Sci 2006, 1068:513-531.
• [3]Kelly DJ, Jacobs CR: The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells. Birth Defects Res C Embryo Today 2010, 90:75-85.
• [4]McCullen SD, Haslauer CM, Loboa EG: Musculoskeletal mechanobiology: interpretation by external force and engineered substratum. J Biomech 2010, 43:119-127.
• [5]Wescoe KE, Schugar RC, Chu CR, Deasy BM: The role of the biochemical and biophysical environment in chondrogenic stem cell differentiation assays and cartilage tissue engineering. Cell Biochem Biophys 2008, 52:85-102.
• [6]Elder BD, Athanasiou KA: Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. Tissue Eng Part B Rev 2009, 15:43-53.
• [7]Grad S, Eglin D, Alini M, Stoddart MJ: Physical stimulation of chondrogenic cells in vitro: a review. Clin Orthop Relat Res 2011, 469:2764-2772.
• [8]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284:143-147.
• [9]Guilak F, Estes BT, Diekman BO, Moutos FT, Gimble JM: Nicolas Andry Award: multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering. Clin Orthop Relat Res 2010, 2010(468):2530-2540.
• [10]De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001, 44:1928-1942.
• [11]Tae SK, Lee SH, Park JS, Im GI: Mesenchymal stem cells for tissue engineering and regenerative medicine. Biomed Mater 2006, 1:63-71.
• [12]Matsumoto T, Okabe T, Ikawa T, Iida T, Yasuda H, Nakamura H, Wakitani S: Articular cartilage repair with autologous bone marrow mesenchymal cells. J Cell Physiol 2010, 225:291-295.
• [13]Estes BT, Diekman BO, Gimble JM, Guilak F: Isolation of adipose-derived stem cells and their induction to a chondrogenic phenotype. Nat Protoc 2010, 5:1294-1311.
• [14]Fan J, Varshney RR, Ren L, Cai D, Wang DA: Synovium-derived mesenchymal stem cells: a new cell source for musculoskeletal regeneration. Tissue Eng Part B Rev 2009, 15:75-86.
• [15]Guilak F, Butler DL, Goldstein SA: Functional tissue engineering: the role of biomechanics in articular cartilage repair. Clin Orthop Relat Res 2001, 391(Suppl):S295-S305.
• [16]Mouw JK, Connelly JT, Wilson CG, Michael KE, Levenston ME: Dynamic compression regulates the expression and synthesis of chondrocyte-specific matrix molecules in bone marrow stromal cells. Stem Cells 2007, 25:655-663.
• [17]Mauck RL, Byers BA, Yuan X, Tuan RS: Regulation of cartilaginous ECM gene transcription by chondrocytes and MSCs in 3D culture in response to dynamic loading. Biomech Model Mechanobiol 2007, 6:113-125.
• [18]Kisiday JD, Frisbie DD, McIlwraith CW, Grodzinsky AJ: Dynamic compression stimulates proteoglycan synthesis by mesenchymal stem cells in the absence of chondrogenic cytokines. Tissue Eng Part A 2009, 15:2817-2824.
• [19]Huang AH, Farrell MJ, Kim M, Mauck RL: Long-term dynamic loading improves the mechanical properties of chondrogenic mesenchymal stem cell-laden hydrogel. Eur Cell Mater 2010, 19:72-85.
• [20]Li Z, Yao SJ, Alini M, Stoddart MJ: Chondrogenesis of human bone marrow mesenchymal stem cells in fibrin-polyurethane composites is modulated by frequency and amplitude of dynamic compression and shear stress. Tissue Eng Part A 2010, 16:575-584.
• [21]Thorpe SD, Buckley CT, Vinardell T, O’Brien FJ, Campbell VA, Kelly DJ: The response of bone marrow-derived mesenchymal stem cells to dynamic compression following TGF-β3 induced chondrogenic differentiation. Ann Biomed Eng 2010, 38:2896-2909.
• [22]Schatti O, Grad S, Goldhahn J, Salzmann G, Li Z, Alini M, Stoddart MJ: A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mesenchymal stem cells. Eur Cell Mater 2011, 22:214-225.
• [23]Haugh MG, Meyer EG, Thorpe SD, Vinardell T, Duffy GP, Kelly DJ: Temporal and spatial changes in cartilage-matrix-specific gene expression in mesenchymal stem cells in response to dynamic compression. Tissue Eng Part A 2011, 17:3085-3093.
• [24]Huang AH, Baker BM, Ateshian GA, Mauck RL: Sliding contact loading enhances the tensile properties of mesenchymal stem cell-seeded hydrogels. Eur Cell Mater 2012, 24:29-45.
• [25]Bian L, Zhai DY, Zhang EC, Mauck RL, Burdick JA: Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels. Tissue Eng Part A 2012, 18:715-724.
• [26]Potier E, Noailly J, Ito K: Directing bone marrow-derived stromal cell function with mechanics. J Biomech 2010, 43:807-817.
• [27]Buschmann MD, Gluzband YA, Grodzinsky AJ, Kimura JH, Hunziker EB: Chondrocytes in agarose culture synthesize a mechanically functional extracellular matrix. J Orthop Res 1992, 10:745-758.
• [28]Lee DA, Bader DL: The development and characterization of an in vitro system to study strain-induced cell deformation in isolated chondrocytes. In Vitro Cell Dev Biol Anim 1995, 31:828-835.
• [29]Byers BA, Mauck RL, Chiang IE, Tuan RS: Transient exposure to transforming growth factor beta 3 under serum-free conditions enhances the biomechanical and biochemical maturation of tissue-engineered cartilage. Tissue Eng Part A 2008, 14:1821-1834.
• [30]Mauck RL, Nicoll SB, Seyhan SL, Ateshian GA, Hung CT: Synergistic action of growth factors and dynamic loading for articular cartilage tissue engineering. Tissue Eng 2003, 9:597-611.
• [31]Kelly TA, Fisher MB, Oswald ES, Tai T, Mauck RL, Ateshian GA, Hung CT: Low-serum media and dynamic deformational loading in tissue engineering of articular cartilage. Ann Biomed Eng 2008, 36:769-779.
• [32]eCM Journal. http://www.ecmjournal.org webcite
• [33]Ng KW, Mauck RL, Wang CC, Kelly TA, Ho MM, Chen FH, Ateshian GA, Hung CT: Duty cycle of deformational loading influences the growth of engineered articular cartilage. Cell Mol Bioeng 2009, 2:386-394.
• [34]Elder SH, Goldstein SA, Kimura JH, Soslowsky LJ, Spengler DM: Chondrocyte differentiation is modulated by frequency and duration of cyclic compressive loading. Ann Biomed Eng 2001, 29:476-482.
• [35]Struglics A, Hansson M: MMP proteolysis of the human extracellular matrix protein aggrecan is mainly a process of normal turnover. Biochem J 2012, 446:213-223.
• [36]Lima EG, Bian L, Ng KW, Mauck RL, Byers BA, Tuan RS, Ateshian GA, Hung CT: The beneficial effect of delayed compressive loading on tissue-engineered cartilage constructs cultured with TGF-β3. Osteoarthr Cartil 2007, 15:1025-1033.
• [37]Pelttari K, Winter A, Steck E, Goetzke K, Hennig T, Ochs BG, Aigner T, Richter W: Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum 2006, 54:3254-3266.
• [38]Guilak F, Mow VC: The mechanical environment of the chondrocyte: a biphasic finite element model of cell-matrix interactions in articular cartilage. J Biomech 2000, 33:1663-1673.
• [39]Waldman SD, Couto DC, Grynpas MD, Pilliar RM, Kandel RA: Multi-axial mechanical stimulation of tissue engineered cartilage: review. Eur Cell Mater 2007, 13:66-73. discussion 73–64
• [40]Guilak F: Compression-induced changes in the shape and volume of the chondrocyte nucleus. J Biomech 1995, 28:1529-1541.
• [41]Bryant SJ, Anseth KS, Lee DA, Bader DL: Crosslinking density influences the morphology of chondrocytes photoencapsulated in PEG hydrogels during the application of compressive strain. J Orthop Res 2004, 22:1143-1149.
• [42]Freeman PM, Natarajan RN, Kimura JH, Andriacchi TP: Chondrocyte cells respond mechanically to compressive loads. J Orthop Res 1994, 12:311-320.
• [43]Choi JB, Youn I, Cao L, Leddy HA, Gilchrist CL, Setton LA, Guilak F: Zonal changes in the three-dimensional morphology of the chondron under compression: the relationship among cellular, pericellular, and extracellular deformation in articular cartilage. J Biomech 2007, 40:2596-2603.
• [44]Kuo CK, Tuan RS: Mechanoactive tenogenic differentiation of human mesenchymal stem cells. Tissue Eng Part A 2008, 14:1615-1627.
• [45]Connelly JT, Vanderploeg EJ, Mouw JK, Wilson CG, Levenston ME: Tensile loading modulates bone marrow stromal cell differentiation and the development of engineered fibrocartilage constructs. Tissue Eng Part A 2010, 16:1913-1923.
• [46]Baker BM, Shah RP, Huang AH, Mauck RL: Dynamic tensile loading improves the functional properties of mesenchymal stem cell-laden nanofiber-based fibrocartilage. Tissue Eng Part A 2011, 17:1445-1455.
• [47]Soltz MA, Ateshian GA: Interstitial fluid pressurization during confined compression cyclical loading of articular cartilage. Ann Biomed Eng 2000, 28:150-159.
• [48]Hall AC, Urban JP, Gehl KA: The effects of hydrostatic pressure on matrix synthesis in articular cartilage. J Orthop Res 1991, 9:1-10.
• [49]Hung CT, Mauck RL, Wang CC, Lima EG, Ateshian GA: A paradigm for functional tissue engineering of articular cartilage via applied physiologic deformational loading. Ann Biomed Eng 2004, 32:35-49.
• [50]Park S, Krishnan R, Nicoll SB, Ateshian GA: Cartilage interstitial fluid load support in unconfined compression. J Biomech 2003, 36:1785-1796.
• [51]Bachrach NM, Mow VC, Guilak F: Incompressibility of the solid matrix of articular cartilage under high hydrostatic pressures. J Biomech 1998, 31:445-451.
• [52]Toyoda T, Seedhom BB, Kirkham J, Bonass WA: Upregulation of aggrecan and type II collagen mRNA expression in bovine chondrocytes by the application of hydrostatic pressure. Biorheology 2003, 40:79-85.
• [53]Elder BD, Athanasiou KA: Synergistic and additive effects of hydrostatic pressure and growth factors on tissue formation. PLoS One 2008, 3:e2341.
• [54]Angele P, Yoo JU, Smith C, Mansour J, Jepsen KJ, Nerlich M, Johnstone B: Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro. J Orthop Res 2003, 21:451-457.
• [55]Miyanishi K, Trindade MC, Lindsey DP, Beaupre GS, Carter DR, Goodman SB, Schurman DJ, Smith RL: Effects of hydrostatic pressure and transforming growth factor-beta 3 on adult human mesenchymal stem cell chondrogenesis in vitro. Tissue Eng 2006, 12:1419-1428.
• [56]Wagner DR, Lindsey DP, Li KW, Tummala P, Chandran SE, Smith RL, Longaker MT, Carter DR, Beaupre GS: Hydrostatic pressure enhances chondrogenic differentiation of human bone marrow stromal cells in osteochondrogenic medium. Ann Biomed Eng 2008, 36:813-820.
• [57]Miyanishi K, Trindade MC, Lindsey DP, Beaupre GS, Carter DR, Goodman SB, Schurman DJ, Smith RL: Dose- and time-dependent effects of cyclic hydrostatic pressure on transforming growth factor-beta3-induced chondrogenesis by adult human mesenchymal stem cells in vitro. Tissue Eng 2006, 12:2253-2262.
• [58]Finger AR, Sargent CY, Dulaney KO, Bernacki SH, Loboa EG: Differential effects on messenger ribonucleic acid expression by bone marrow-derived human mesenchymal stem cells seeded in agarose constructs due to ramped and steady applications of cyclic hydrostatic pressure. Tissue Eng 2007, 13:1151-1158.
• [59]Puetzer J, Williams J, Gillies A, Bernacki S, Loboa EG: The effects of cyclic hydrostatic pressure on chondrogenesis and viability of human adipose- and bone marrow-derived mesenchymal stem cells in three-dimensional agarose constructs. Tissue Eng Part A 2013, 19:299-306.
• [60]Li J, Zhao Z, Yang J, Liu J, Wang J, Li X, Liu Y: p38 MAPK mediated in compressive stress-induced chondrogenesis of rat bone marrow MSCs in 3D alginate scaffolds. J Cell Physiol 2009, 221:609-617.
• [61]Li J, Wang J, Zou Y, Zhang Y, Long D, Lei L, Tan L, Ye R, Wang X, Zhao Z: The influence of delayed compressive stress on TGF-β1-induced chondrogenic differentiation of rat BMSCs through Smad-dependent and Smad-independent pathways. Biomaterials 2012, 33:8395-8405.
• [62]Urban JP, Hall AC, Gehl KA: Regulation of matrix synthesis rates by the ionic and osmotic environment of articular chondrocytes. J Cell Physiol 1993, 154:262-270.
• [63]Hopewell B, Urban JP: Adaptation of articular chondrocytes to changes in osmolality. Biorheology 2003, 40:73-77.
• [64]Negoro K, Kobayashi S, Takeno K, Uchida K, Baba H: Effect of osmolarity on glycosaminoglycan production and cell metabolism of articular chondrocyte under three-dimensional culture system. Clin Exp Rheumatol 2008, 26:534-541.
• [65]Xu X, Urban JP, Tirlapur UK, Cui Z: Osmolarity effects on bovine articular chondrocytes during three-dimensional culture in alginate beads. Osteoarthr Cartil 2010, 18:433-439.
• [66]Oswald ES, Ahmed HS, Kramer SP, Bulinski JC, Ateshian GA, Hung CT: Effects of hypertonic (NaCl) two-dimensional and three-dimensional culture conditions on the properties of cartilage tissue engineered from an expanded mature bovine chondrocyte source. Tissue Eng Part C Methods 2011, 17:1041-1049.
• [67]Tew SR, Peffers MJ, McKay TR, Lowe ET, Khan WS, Hardingham TE, Clegg PD: Hyperosmolarity regulates SOX9 mRNA posttranscriptionally in human articular chondrocytes. Am J Physiol Cell Physiol 2009, 297:C898-C906.
• [68]Peffers MJ, Milner PI, Tew SR, Clegg PD: Regulation of SOX9 in normal and osteoarthritic equine articular chondrocytes by hyperosmotic loading. Osteoarthr Cartil 2010, 18:1502-1508.
• [69]Coleman JL, Widmyer MR, Leddy HA, Utturkar GM, Spritzer CE, Moorman CT 3rd, Guilak F, Defrate LE: Diurnal variations in articular cartilage thickness and strain in the human knee. J Biomech 2013, 46:541-547.
• [70]Chao PH, West AC, Hung CT: Chondrocyte intracellular calcium, cytoskeletal organization, and gene expression responses to dynamic osmotic loading. Am J Physiol Cell Physiol 2006, 291:C718-C725.
• [71]Wuertz K, Godburn K, Neidlinger-Wilke C, Urban J, Iatridis JC: Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc. Spine (Phila Pa 1976) 2008, 33:1843-1849.
• [72]Liang C, Li H, Tao Y, Zhou X, Li F, Chen G, Chen Q: Responses of human adipose-derived mesenchymal stem cells to chemical microenvironment of the intervertebral disc. J Transl Med 2012, 10:49. BioMed Central Full Text
• [73]Caron MM, van der Windt AE, Emans PJ, van Rhijn LW, Jahr H, Welting TJ: Osmolarity determines the in vitro chondrogenic differentiation capacity of progenitor cells via nuclear factor of activated T-cells 5. Bone 2013, 53:94-102.
• [74]Albro MB, Cigan AD, Nims RJ, Yeroushalmi KJ, Oungoulian SR, Hung CT, Ateshian GA: Shearing of synovial fluid activates latent TGF-beta. Osteoarthr Cartil 2012, 20:1374-1382.
• [75]Vunjak-Novakovic G, Martin I, Obradovic B, Treppo S, Grodzinsky AJ, Langer R, Freed LE: Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J Orthop Res 1999, 17:130-138.
• [76]Pazzano D, Mercier KA, Moran JM, Fong SS, DiBiasio DD, Rulfs JX, Kohles SS, Bonassar LJ: Comparison of chondrogensis in static and perfused bioreactor culture. Biotechnol Prog 2000, 16:893-896.
• [77]Vunjak-Novakovic G, Obradovic B, Martin I, Freed LE: Bioreactor studies of native and tissue engineered cartilage. Biorheology 2002, 39:259-268.
• [78]Goncalves A, Costa P, Rodrigues MT, Dias IR, Reis RL, Gomes ME: Effect of flow perfusion conditions in the chondrogenic differentiation of bone marrow stromal cells cultured onto starch based biodegradable scaffolds. Acta Biomater 2011, 7:1644-1652.
• [79]da Silva ML A, Martins A, Costa-Pinto AR, Correlo VM, Sol P, Bhattacharya M, Faria S, Reis RL, Neves NM: Chondrogenic differentiation of human bone marrow mesenchymal stem cells in chitosan-based scaffolds using a flow-perfusion bioreactor. J Tissue Eng Regen Med 2011, 5:722-732.
• [80]Valonen PK, Moutos FT, Kusanagi A, Moretti MG, Diekman BO, Welter JF, Caplan AI, Guilak F, Freed LE: In vitro generation of mechanically functional cartilage grafts based on adult human stem cells and 3D-woven poly(epsilon-caprolactone) scaffolds. Biomaterials 2010, 31:2193-2200.
• [81]Barrett-Jolley R, Lewis R, Fallman R, Mobasheri A: The emerging chondrocyte channelome. Front Physiol 2010, 1:135.
• [82]Phan MN, Leddy HA, Votta BJ, Kumar S, Levy DS, Lipshutz DB, Lee SH, Liedtke W, Guilak F: Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum 2009, 60:3028-3037.
• [83]Browning JA, Saunders K, Urban JP, Wilkins RJ: The influence and interactions of hydrostatic and osmotic pressures on the intracellular milieu of chondrocytes. Biorheology 2004, 41:299-308.
• [84]Han SK, Wouters W, Clark A, Herzog W: Mechanically induced calcium signaling in chondrocytes in situ. J Orthop Res 2012, 30:475-481.
• [85]Pingguan-Murphy B, El-Azzeh M, Bader DL, Knight MM: Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate- and frequency-dependent manner. J Cell Physiol 2006, 209:389-397.
• [86]Fitzgerald JB, Jin M, Grodzinsky AJ: Shear and compression differentially regulate clusters of functionally related temporal transcription patterns in cartilage tissue. J Biol Chem 2006, 281:24095-24103.
• [87]Mouw JK, Imler SM, Levenston ME: Ion-channel regulation of chondrocyte matrix synthesis in 3D culture under static and dynamic compression. Biomech Model Mechanobiol 2007, 6:33-41.
• [88]Natoli RM, Skaalure S, Bijlani S, Chen KX, Hu J, Athanasiou KA: Intracellular Na(+) and Ca(2+) modulation increases the tensile properties of developing engineered articular cartilage. Arthritis Rheum 2010, 62:1097-1107.
• [89]Hoey DA, Downs ME, Jacobs CR: The mechanics of the primary cilium: an intricate structure with complex function. J Biomech 2012, 45:17-26.
• [90]Wilsman NJ: Cilia of adult canine articular chondrocytes. J Ultrastruct Res 1978, 64:270-281.
• [91]Poole CA, Flint MH, Beaumont BW: Analysis of the morphology and function of primary cilia in connective tissues: a cellular cybernetic probe? Cell Motil 1985, 5:175-193.
• [92]Whitfield JF: The solitary (primary) cilium – a mechanosensory toggle switch in bone and cartilage cells. Cell Signal 2008, 20:1019-1024.
• [93]Muhammad H, Rais Y, Miosge N, Ornan EM: The primary cilium as a dual sensor of mechanochemical signals in chondrocytes. Cell Mol Life Sci 2012, 69:2101-2107.
• [94]McGlashan SR, Jensen CG, Poole CA: Localization of extracellular matrix receptors on the chondrocyte primary cilium. J Histochem Cytochem 2006, 54:1005-1014.
• [95]Wann AK, Zuo N, Haycraft CJ, Jensen CG, Poole CA, McGlashan SR, Knight MM: Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes. FASEB J 2012, 26:1663-1671.
• [96]Martins RP, Finan JD, Guilak F, Lee DA: Mechanical regulation of nuclear structure and function. Annu Rev Biomed Eng 2012, 14:431-455.
• [97]Lee DA, Knight MM, Bolton JF, Idowu BD, Kayser MV, Bader DL: Chondrocyte deformation within compressed agarose constructs at the cellular and sub-cellular levels. J Biomech 2000, 33:81-95.
• [98]Finan JD, Chalut KJ, Wax A, Guilak F: Nonlinear osmotic properties of the cell nucleus. Ann Biomed Eng 2009, 37:477-491.
• [99]Finan JD, Guilak F: The effects of osmotic stress on the structure and function of the cell nucleus. J Cell Biochem 2010, 109:460-467.
• [100]Blain EJ: Involvement of the cytoskeletal elements in articular cartilage homeostasis and pathology. Int J Exp Pathol 2009, 90:1-15.
• [101]Trickey WR, Vail TP, Guilak F: The role of the cytoskeleton in the viscoelastic properties of human articular chondrocytes. J Orthop Res 2004, 22:131-139.
• [102]Erickson GR, Northrup DL, Guilak F: Hypo-osmotic stress induces calcium-dependent actin reorganization in articular chondrocytes. Osteoarthr Cartil 2003, 11:187-197.
• [103]Knight MM, Toyoda T, Lee DA, Bader DL: Mechanical compression and hydrostatic pressure induce reversible changes in actin cytoskeletal organisation in chondrocytes in agarose. J Biomech 2006, 39:1547-1551.
• [104]Giannoni P, Siegrist M, Hunziker EB, Wong M: The mechanosensitivity of cartilage oligomeric matrix protein (COMP). Biorheology 2003, 40:101-109.
• [105]Chowdhury TT, Appleby RN, Salter DM, Bader DA, Lee DA: Integrin-mediated mechanotransduction in IL-1 beta stimulated chondrocytes. Biomech Model Mechanobiol 2006, 5:192-201.
• [106]Chai DH, Arner EC, Griggs DW, Grodzinsky AJ: Alphav and beta1 integrins regulate dynamic compression-induced proteoglycan synthesis in 3D gel culture by distinct complementary pathways. Osteoarthr Cartil 2010, 18:249-256.
• [107]Wang JH, Thampatty BP: An introductory review of cell mechanobiology. Biomech Model Mechanobiol 2006, 5:1-16.