title: Articular cartilage tissue engineering: the role of signaling molecules.
abstract: Effective early disease modifying options for osteoarthritis remain lacking. Tissue engineering approach to generate cartilage in vitro has emerged as a promising option for articular cartilage repair and regeneration. Signaling molecules and matrix modifying agents, derived from knowledge of cartilage development and homeostasis, have been used as biochemical stimuli toward cartilage tissue engineering and have led to improvements in the functionality of engineered cartilage. Clinical translation of neocartilage faces challenges, such as phenotypic instability of the engineered cartilage, poor integration, inflammation, and catabolic factors in the arthritic environment; these can all contribute to failure of implanted neocartilage. A comprehensive understanding of signaling molecules involved in osteoarthritis pathogenesis and their actions on engineered cartilage will be crucial. Thus, while it is important to continue deriving inspiration from cartilage development and homeostasis, it has become increasingly necessary to incorporate knowledge from osteoarthritis pathogenesis into cartilage tissue engineering.
authors.affiliation: Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
authors.forename: Heenam
authors.initials: H
authors.lastname: Kwon
authors.affiliation: Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Paschos
authors.affiliation: Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Hu
authors.affiliation: Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA. athanasiou@ucdavis.edu.|Department of Orthopaedic Surgery, University of California Davis Medical Center, Sacramento, CA, USA. athanasiou@ucdavis.edu.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Athanasiou
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000254:growth & development* / Q000378:metabolism* / Q000503:physiopathology; D020219:Chondrogenesis; D006801:Humans; D010003:Osteoarthritis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods*
keywords: Articular cartilage; Cartilage development; Osteoarthritis; Signaling molecules; Tissue engineering
references.citation: PLoS Genet. 2011 Nov;7(11):e1002356
references.pmid: 22072985
references.citation: Tissue Cell. 2012 Apr;44(2):69-73
references.pmid: 22185680
references.citation: Eur Cell Mater. 2014 Apr 23;27:312-20
references.pmid: 24760578
references.citation: Arthritis Rheum. 2009 Mar;60(3):801-12
references.pmid: 19248089
references.citation: Genome Biol. 2001;2(3):REVIEWS3005
references.pmid: 11276432
references.citation: PLoS One. 2014 May 27;9(5):e98570
references.pmid: 24867063
references.citation: J Cell Physiol. 2005 May;203(2):398-409
references.pmid: 15521064
references.citation: Development. 1994 Jan;120(1):177-87
references.pmid: 8119125
references.citation: Dev Cell. 2001 Aug;1(2):277-90
references.pmid: 11702786
references.citation: Osteoarthritis Cartilage. 2013 Nov;21(11):1627-37
references.pmid: 23933379
references.citation: Ann Biomed Eng. 2004 Jan;32(1):50-6
references.pmid: 14964721
references.citation: Arthritis Rheum. 2003 Aug;48(8):2188-96
references.pmid: 12905472
references.citation: Dev Biol. 1989 Oct;135(2):424-30
references.pmid: 2776976
references.citation: J Orthop Res. 2001 Nov;19(6):1089-97
references.pmid: 11781010
references.citation: Endocrinology. 2001 Jan;142(1):430-6
references.pmid: 11145607
references.citation: Nat Genet. 1996 Oct;14(2):174-6
references.pmid: 8841188
references.citation: Mech Dev. 1998 Sep;77(1):19-30
references.pmid: 9784595
references.citation: Osteoarthritis Cartilage. 2008 Oct;16(10):1121-30
references.pmid: 18406633
references.citation: Stem Cell Rev Rep. 2015 Apr;11(2):242-53
references.pmid: 25578634
references.citation: J Cell Biochem. 2001 Mar 26;81(2):368-77
references.pmid: 11241676
references.citation: Adv Pharmacol. 2006;53:253-79
references.pmid: 17239770
references.citation: J Bone Miner Res. 2006 Apr;21(4):626-36
references.pmid: 16598383
references.citation: J Bone Joint Surg Br. 1998 Jan;80(1):144-50
references.pmid: 9460972
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Dev Biol. 1989 Nov;136(1):97-103
references.pmid: 2806726
references.citation: Int J Biochem Cell Biol. 2009 May;41(5):1198-204
references.pmid: 19041414
references.citation: Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):E4832-41
references.pmid: 25349395
references.citation: PLoS One. 2013;8(2):e56983
references.pmid: 23437288
references.citation: Acta Med Okayama. 2010 Dec;64(6):351-7
references.pmid: 21173804
references.citation: J Bone Miner Res. 1998 Mar;13(3):383-92
references.pmid: 9525338
references.citation: J Bone Joint Surg Am. 2001;83-A Suppl 1(Pt 1):S15-22
references.pmid: 11263661
references.citation: PLoS One. 2014 Feb 13;9(2):e89025
references.pmid: 24551211
references.citation: Genes Dev. 2004 May 1;18(9):1072-87
references.pmid: 15132997
references.citation: Science. 2009 May 8;324(5928):797-801
references.pmid: 19325077
references.citation: J Mol Med (Berl). 2012 Jun;90(6):649-66
references.pmid: 22215151
references.citation: J Dent Res. 2009 Aug;88(8):693-703
references.pmid: 19734454
references.citation: Stem Cells. 2007 Sep;25(9):2183-90
references.pmid: 17540854
references.citation: Nature. 1994 Sep 15;371(6494):252-4
references.pmid: 8078586
references.citation: Nature. 1982 Mar 18;296(5854):252-3
references.pmid: 7038514
references.citation: Osteoarthritis Cartilage. 2013 Apr;21(4):634-41
references.pmid: 23353112
references.citation: Genes Dev. 1994 Dec 15;8(24):3045-57
references.pmid: 8001823
references.citation: J Biol Chem. 2003 Oct 17;278(42):41227-36
references.pmid: 12893825
references.citation: Tissue Eng. 2002 Aug;8(4):591-601
references.pmid: 12201999
references.citation: Biochem Biophys Res Commun. 2008 Aug 15;373(1):104-8
references.pmid: 18554504
references.citation: J Cell Biochem. 2013 Feb;114(2):480-90
references.pmid: 22961870
references.citation: Tissue Eng Part A. 2012 Jun;18(11-12):1161-70
references.pmid: 22429262
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2013 Oct;33(5):700-706
references.pmid: 24142723
references.citation: Tissue Eng Part A. 2010 Nov;16(11):3449-55
references.pmid: 20569194
references.citation: Genes Dev. 2002 Nov 1;16(21):2813-28
references.pmid: 12414734
references.citation: Osteoarthritis Cartilage. 2000 Sep;8(5):309-34
references.pmid: 10966838
references.citation: J Bone Miner Res. 1999 Oct;14(10):1734-41
references.pmid: 10491221
references.citation: Arthritis. 2012;2012:741582
references.pmid: 22745906
references.citation: Mol Endocrinol. 2003 Jul;17(7):1332-43
references.pmid: 12677004
references.citation: Tissue Eng Part A. 2014 Dec;20(23-24):3332-41
references.pmid: 24947008
references.citation: Arthritis Rheum. 2009 Dec;60(12):3686-92
references.pmid: 19950276
references.citation: Biochim Biophys Acta. 2014 Aug;1840(8):2414-40
references.pmid: 24608030
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6698-703
references.pmid: 11371614
references.citation: J Orthop Res. 1999 Jan;17(1):110-20
references.pmid: 10073655
references.citation: J Biol Chem. 2003 Sep 19;278(38):36563-71
references.pmid: 12853454
references.citation: Int Orthop. 2007 Dec;31(6):773-81
references.pmid: 17687553
references.citation: J Bone Miner Res. 2011 Jul;26(7):1437-46
references.pmid: 21312270
references.citation: Stem Cells. 2009 Nov;27(11):2667-74
references.pmid: 19697349
references.citation: Eur Cell Mater. 2008 Sep 03;16:26-39
references.pmid: 18770504
references.citation: Cell Tissue Res. 2005 May;320(2):269-76
references.pmid: 15778851
references.citation: Stem Cell Reports. 2015 Mar 10;4(3):404-18
references.pmid: 25733017
references.citation: Development. 2005 Feb;132(3):515-28
references.pmid: 15634692
references.citation: Cytotherapy. 2007;9(2):184-93
references.pmid: 17453970
references.citation: Clin Orthop Relat Res. 2004 Oct;(427 Suppl):S27-36
references.pmid: 15480070
references.citation: J Cell Biol. 2001 Apr 2;153(1):35-46
references.pmid: 11285272
references.citation: Acta Physiol Scand. 1999 May;166(1):39-45
references.pmid: 10372977
references.citation: J Orthop Res. 1996 Nov;14(6):937-45
references.pmid: 8982137
references.citation: J Bone Miner Res. 2000 Jan;15(1):166-74
references.pmid: 10646126
references.citation: Dev Biol. 2007 Jul 15;307(2):300-13
references.pmid: 17544391
references.citation: Tissue Eng Part A. 2009 Oct;15(10):3119-28
references.pmid: 19344291
references.citation: Tissue Eng Part A. 2010 May;16(5):1633-43
references.pmid: 19995150
references.citation: J Tissue Eng Regen Med. 2008 Oct;2(7):418-29
references.pmid: 18727135
references.citation: Tissue Eng Part A. 2009 Jul;15(7):1543-51
references.pmid: 19072523
references.citation: Nat Rev Rheumatol. 2013 Dec;9(12):721-30
references.pmid: 24080861
references.citation: Arthritis Rheum. 1992 Jul;35(7):806-11
references.pmid: 1622419
references.citation: J Orthop Res. 1989;7(5):619-36
references.pmid: 2760736
references.citation: Development. 1992 Jan;114(1):233-43
references.pmid: 1315677
references.citation: J Clin Invest. 1986 Jun;77(6):1903-8
references.pmid: 3519682
references.citation: Biomaterials. 2012 Jan;33(1):109-19
references.pmid: 21959004
references.citation: Tissue Eng Part B Rev. 2014 Oct;20(5):381-91
references.pmid: 24206162
references.citation: Cells Tissues Organs. 2010;191(2):105-18
references.pmid: 19641298
references.citation: Annu Rev Cell Dev Biol. 2009;25:629-48
references.pmid: 19575648
references.citation: Exp Cell Res. 1999 Aug 1;250(2):351-63
references.pmid: 10413589
references.citation: J Cell Biochem. 2010 Dec 15;111(6):1642-51
references.pmid: 21053273
references.citation: Stem Cells. 2015 Mar;33(3):762-73
references.pmid: 25377511
references.citation: Osteoarthritis Cartilage. 2008 Dec;16(12):1450-6
references.pmid: 18541445
references.citation: Nat Genet. 1994 Sep;8(1):98-103
references.pmid: 7987400
references.citation: Nat Rev Rheumatol. 2011 Sep 27;7(11):654-63
references.pmid: 21947178
references.citation: Biomaterials. 2012 Apr;33(11):3187-94
references.pmid: 22284584
references.citation: EMBO J. 2001 May 1;20(9):2254-72
references.pmid: 11331591
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):472-6
references.pmid: 19481515
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):75-82
references.pmid: 19197334
references.citation: J Cell Physiol. 2001 Dec;189(3):275-84
references.pmid: 11748585
references.citation: Genes Dev. 2002 Jun 15;16(12):1446-65
references.pmid: 12080084
references.citation: Biomaterials. 2014 Dec;35(36):9599-607
references.pmid: 25176059
references.citation: Nat Rev Drug Discov. 2005 Apr;4(4):331-44
references.pmid: 15803196
references.citation: Osteoarthritis Cartilage. 2005 Aug;13(8):709-15
references.pmid: 16043034
references.citation: Arch Biochem Biophys. 2000 Feb 15;374(2):172-80
references.pmid: 10666295
references.citation: PLoS One. 2013 Oct 16;8(10):e77365
references.pmid: 24146984
references.citation: Tissue Eng Part A. 2009 Oct;15(10):3025-36
references.pmid: 19335060
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19004-9
references.pmid: 17142326
references.citation: Tissue Eng Part A. 2009 May;15(5):1151-8
references.pmid: 18831685
references.citation: PLoS One. 2011;6(12):e28663
references.pmid: 22194879
references.citation: Arthritis Rheum. 2008 Apr;58(4):1067-75
references.pmid: 18383381
references.citation: Stem Cells Dev. 2009 Jul-Aug;18(6):893-906
references.pmid: 18834279
references.citation: Cell. 1994 Jul 29;78(2):335-42
references.pmid: 7913883
references.citation: Arthritis Rheum. 2006 Jan;54(1):226-9
references.pmid: 16385518
references.citation: Semin Arthritis Rheum. 2014 Apr;43(5):579-87
references.pmid: 24262930
references.citation: Nat Genet. 1995 Feb;9(2):165-72
references.pmid: 7719344
references.citation: Osteoarthritis Cartilage. 2009 Jan;17(1):114-23
references.pmid: 18571441
references.citation: J Tissue Eng Regen Med. 2015 Apr;9(4):332-42
references.pmid: 23576364
references.citation: J Cell Physiol. 1999 Feb;178(2):197-204
references.pmid: 10048584
references.citation: Bone Res. 2014 Apr 29;2:14003
references.pmid: 26273516
references.citation: J Cell Biochem. 2013 Apr;114(4):735-42
references.pmid: 23060229
references.citation: J Biomed Mater Res A. 2010 Aug;94(2):539-46
references.pmid: 20186773
references.citation: Tissue Eng Part A. 2012 Jan;18(1-2):45-54
references.pmid: 21770865
references.citation: Tissue Eng Part A. 2011 Apr;17(7-8):991-1002
references.pmid: 21091327
references.citation: J Biol Chem. 2005 Apr 22;280(16):15872-9
references.pmid: 15703179
references.citation: Bone. 2004 May;34(5):809-17
references.pmid: 15121012
references.citation: J Orthop Res. 2005 May;23(3):594-601
references.pmid: 15885480
references.citation: J Cell Physiol. 1993 Aug;156(2):399-411
references.pmid: 8344994
references.citation: J Biol Chem. 2004 Jan 16;279(3):1747-56
references.pmid: 14593093
references.citation: J Orthop Res. 2009 Jul;27(7):949-56
references.pmid: 19123232
references.citation: Arthritis Rheum. 2005 Dec;52(12):3910-7
references.pmid: 16320338
references.citation: Cell Tissue Res. 2005 Dec;322(3):463-73
references.pmid: 16047167
references.citation: Arthritis Rheum. 2007 Jan;56(1):188-98
references.pmid: 17195221
references.citation: Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12097-102
references.pmid: 25092332
references.citation: J Biomech. 2015 Sep 18;48(12):3406-12
references.pmid: 26117076
references.citation: Arthritis Rheum. 2008 Jan;58(1):26-35
references.pmid: 18163497
references.citation: J Orthop Res. 2001 Jan;19(1):11-7
references.pmid: 11332605
references.citation: Tissue Eng. 2006 Apr;12(4):969-79
references.pmid: 16674308
references.citation: Differentiation. 2008 Dec;76(10):1044-56
references.pmid: 18637024
references.citation: Biomaterials. 2012 Sep;33(26):6042-51
references.pmid: 22677190
references.citation: J Biol Chem. 2005 Mar 4;280(9):8343-50
references.pmid: 15623506
references.citation: Endocrinology. 2006 May;147(5):2171-82
references.pmid: 16439448
references.citation: Cytokine Growth Factor Rev. 2004 Feb;15(1):1-11
references.pmid: 14746809
references.citation: Osteoarthritis Cartilage. 2013 Apr;21(4):604-13
references.pmid: 23353668
references.citation: Endocrinology. 2000 Dec;141(12):4728-35
references.pmid: 11108288
references.citation: Acta Orthop. 2011 Apr;82(2):234-40
references.pmid: 21434761
references.citation: Cancer Res. 2009 Jul 1;69(13):5331-9
references.pmid: 19509230
references.citation: Stem Cells Dev. 2011 Jun;20(6):1099-112
references.pmid: 20846027
references.citation: J Tissue Eng Regen Med. 2009 Feb;3(2):117-23
references.pmid: 19160351
references.citation: Nat Biotechnol. 2007 Feb;25(2):207-15
references.pmid: 17287758
references.citation: Nat Methods. 2011 May;8(5):409-12
references.pmid: 21460823
references.citation: Biomaterials. 2014 Aug;35(25):6787-96
references.pmid: 24840619
references.citation: J Tissue Eng Regen Med. 2015 Apr;9(4):368-74
references.pmid: 23255524
references.citation: Ann Anat. 2015 Mar;198:1-10
references.pmid: 25621374
references.citation: Bull NYU Hosp Jt Dis. 2007;65(1):51-60
references.pmid: 17539762
references.citation: Stem Cell Rev Rep. 2015 Apr;11(2):228-41
references.pmid: 25618295
references.citation: Osteoarthritis Cartilage. 2008 Mar;16(3):359-66
references.pmid: 17714957
references.citation: PLoS One. 2008 Jun 04;3(6):e2341
references.pmid: 18523560
references.citation: Bone. 2004 Nov;35(5):1069-76
references.pmid: 15542031
references.citation: Endocrinology. 1995 Jun;136(6):2741-51
references.pmid: 7750499
references.citation: EMBO J. 1998 Oct 1;17(19):5718-33
references.pmid: 9755172
references.citation: Arthritis Rheum. 2010 Apr;62(4):1097-107
references.pmid: 20131245
references.citation: Arthritis Res Ther. 2004;6(5):R469-76
references.pmid: 15380046
references.citation: J Orthop Res. 2012 Dec;30(12):1898-905
references.pmid: 22707357
references.citation: Hum Mol Genet. 1995 Mar;4(3):323-8
references.pmid: 7795583
references.citation: J Tissue Eng Regen Med. 2009 Feb;3(2):107-16
references.pmid: 19177463
references.citation: Stem Cells Transl Med. 2015 Apr;4(4):389-400
references.pmid: 25722427
references.citation: J Cell Biol. 1999 Jan 11;144(1):161-73
references.pmid: 9885252
references.citation: Biochem Biophys Res Commun. 2012 Jul 27;424(2):234-8
references.pmid: 22728881
references.citation: Stem Cells Dev. 2013 Jan 1;22(1):102-13
references.pmid: 22817676
references.citation: MMWR Morb Mortal Wkly Rep. 2013 Nov 8;62(44):869-73
references.pmid: 24196662
references.citation: Stem Cells. 2005 Jun-Jul;23(6):727-37
references.pmid: 15917469
references.citation: J Biol Chem. 2001 Sep 21;276(38):35290-6
references.pmid: 11466306
references.citation: Int J Dev Biol. 1999 Jan;43(1):59-67
references.pmid: 10213083
references.citation: Development. 2010 Mar;137(6):901-11
references.pmid: 20179096
references.citation: Tissue Eng. 2006 Jun;12(6):1419-28
references.pmid: 16846340
references.citation: Stem Cells Transl Med. 2015 Oct;4(10):1187-98
references.pmid: 26253713
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1113-8
references.pmid: 10655493
references.citation: Cell Mol Life Sci. 2010 Dec;67(24):4197-211
references.pmid: 20734104
references.citation: Dev Biol. 2007 Feb 1;302(1):80-91
references.pmid: 17014841
references.citation: J Orthop Res. 2009 Feb;27(2):249-56
references.pmid: 18683879
references.citation: Tissue Eng. 2002 Feb;8(1):73-84
references.pmid: 11886656
references.citation: Cell Prolif. 2010 Aug;43(4):333-43
references.pmid: 20590658
references.citation: Nat Genet. 1994 Nov;8(3):269-74
references.pmid: 7874169
references.citation: Nat Genet. 1994 Nov;8(3):275-9
references.pmid: 7874170
references.citation: Int J Dev Biol. 1995 Dec;39(6):881-93
references.pmid: 8901191
references.citation: Arthritis Rheum. 2004 Nov;50(11):3561-73
references.pmid: 15529345
references.citation: J Biomed Mater Res. 1997 Feb;34(2):211-20
references.pmid: 9029301
references.citation: J Cell Biochem. 2006 Jan 1;97(1):84-97
references.pmid: 16088956
references.citation: Biochem Soc Trans. 2005 Dec;33(Pt 6):1526-30
references.pmid: 16246161
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5062-7
references.pmid: 15781876
references.citation: J Clin Invest. 2011 Feb;121(2):640-57
references.pmid: 21293062
references.citation: J Cell Sci. 2007 Aug 15;120(Pt 16):2875-83
references.pmid: 17652163
references.citation: Exp Cell Res. 1997 Dec 15;237(2):318-25
references.pmid: 9434627
references.citation: Tissue Eng. 2003 Aug;9(4):597-611
references.pmid: 13678439
references.citation: Biochem Biophys Res Commun. 2004 Jul 30;320(3):914-9
references.pmid: 15240135
references.citation: Cytotechnology. 2008 Jan;56(1):1-7
references.pmid: 19002835
references.citation: J Control Release. 2015 May 28;206:101-7
references.pmid: 25804870
references.citation: Curr Top Dev Biol. 2006;76:1-48
references.pmid: 17118262
references.citation: J Bone Miner Res. 2002 May;17(5):898-906
references.pmid: 12009021
references.citation: J Bone Joint Surg Br. 2005 Apr;87(4):445-9
references.pmid: 15795189