Anterior cruciate ligament (ACL) tears are a common injury. The healing potential of the injured ACL is poorly understood and is considered limited. Therefore, most ACL tears that are treated surgically undergo reconstruction rather than repair. However, there has been renewed interest recently in repairing ACL tears despite unanswered questions regarding the healing capacity of the ACL.
Hypothesis:
Gene expression in the injured ACL varies with time from injury.
Study Design:
Descriptive laboratory study.
Methods:
Transcriptome-wide expression profiles of 24 human ACL remnants recovered at the time of surgical reconstruction were analyzed using the Agilent human 8x60K microarray platform. Gene ontology was performed on differentially expressed transcripts based on time from injury (acute, <3 months; intermediate, 3-12 months; chronic, >12 months). A subset of transcripts with large fold changes in expression between any 2 categories was validated via microfluidic digital polymerase chain reaction.
Results:
Numerous transcripts representing important biological processes were differentially expressed by time from injury. The most significant changes were noted between the acute and chronic groups. Expression of several extracellular matrix genes— namely, POSTN, COL5A1, COL1A1, and COL12A1—was lower in the chronic tears compared with acute and intermediate tears. In acute tears, processes representing angiogenesis and stem cell differentiation were affected. In intermediate tears, processes representing stem cell proliferation concomitant with cellular component organization/cellular localization were altered. In ACL tears more than 12 months out from injury, processes denoting myosin filament organization, cellular component organization/cell localization, and extracellular matrix organization were affected.
Conclusion:
These findings are consistent with initial repair activity in the injured ACL, which declines with time from injury. Individual genes identified in this study, such as periostin, deserve further investigation into their role in tissue repair.
Clinical Relevance:
The decreased healing capacity of ACL tears over time is relevant to the development of effective techniques for repairing ACL tears and may have some significance for ACL reconstruction techniques as well. The potential for healing appears to be greatest in acute ACL tears, suggesting this window should be the focus of research for ACL repair.
AndersonAFSnyderRBLipscombABJr.Anterior cruciate ligament reconstruction: a prospective randomized study of three surgical methods. Am J Sports Med. 2001;29(3):272-279.
2.
AnderssonCOdenstenMGoodLGillquistJ.Surgical or non-surgical treatment of acute rupture of the anterior cruciate ligament: a randomized study with long-term follow-up. J Bone Joint Surg Am. 1989;71(7):965-974.
3.
BarrettAMCraftJAReplogleWHHydrickJMBarrettGR.Anterior cruciate ligament graft failure: a comparison of graft type based on age and Tegner activity level. Am J Sports Med. 2011;39(10):2194-2198.
4.
BonnetNGineytsEAmmannPConwaySJGarneroPFerrariS.Periostin deficiency increases bone damage and impairs injury response to fatigue loading in adult mice. PLoS One. 2013;8(10):e78347.
5.
BorgTKMarkwaldR.Periostin: more than just an adhesion molecule. Circ Res. 2007;101(3):230-231.
6.
BrayRCLeonardCASaloPT.Correlation of healing capacity with vascular response in the anterior cruciate and medial collateral ligaments of the rabbit. J Orthop Res. 2003;21(6):1118-1123.
7.
BriotAJaroszewiczAWarrenCM. Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells. Dev Cell. 2014;31(6):707-721.
ChamberlainCSBrountsSHSterkenDGRolnickKIBaerGSVanderbyR.Gene profiling of the rat medial collateral ligament during early healing using microarray analysis. J Appl Physiol (1985). 2011;111(2):552-565.
10.
ClementsDNCarterSDInnesJFOllierWEDayPJ.Gene expression profiling of normal and ruptured canine anterior cruciate ligaments. Osteoarthritis Cartilage. 2008;16(2):195-203.
11.
CrawfordJNygardKGanBSO’GormanDB.Periostin induces fibroblast proliferation and myofibroblast persistence in hypertrophic scarring. Exp Dermatol. 2015;24(2):120-126.
12.
DornGWII. Periostin and myocardial repair, regeneration, and recovery. N Engl J Med. 2007;357(15):1552-1554.
13.
FerrettiMLevicoffEAMacphersonTAMorelandMSCohenMFuFH.The fetal anterior cruciate ligament: an anatomic and histologic study. Arthroscopy. 2007;23(3):278-283.
14.
GeZGohJCLeeEH.The effects of bone marrow-derived mesenchymal stem cells and fascia wrap application to anterior cruciate ligament tissue engineering. Cell Transplant. 2005;14(10):763-773.
15.
GoetschSCHawkeTJGallardoTDRichardsonJAGarryDJ.Transcriptional profiling and regulation of the extracellular matrix during muscle regeneration. Physiol Genomics. 2003;14(3):261-271.
16.
Granero-MoltoFWeisJAMigaMI. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. 2009;27(8):1887-1898.
17.
HaslauerCMElsaidKAFlemingBCProffenBLJohnsonVMMurrayMM.Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury. Osteoarthritis Cartilage. 2013;21(12):1950-1957.
18.
HaslauerCMProffenBLJohnsonVMMurrayMM.Expression of modulators of extracellular matrix structure after anterior cruciate ligament injury. Wound Repair Regen. 2014;22(1):103-110.
19.
HorieMSekiyaIMunetaT. Intra-articular Injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect. Stem Cells. 2009;27(4):878-887.
20.
HoriuchiKAmizukaNTakeshitaS. Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta. J Bone Miner Res. 1999;14(7):1239-1249.
21.
JuYJMunetaTYoshimuraHKogaHSekiyaI.Synovial mesenchymal stem cells accelerate early remodeling of tendon-bone healing. Cell Tissue Res. 2008;332(3):469-478.
22.
KanayaADeieMAdachiNNishimoriMYanadaSOchiM.Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy. 2007;23(6):610-617.
23.
KennedyJJacksonMPO’KellyPMoranR.Timing of reconstruction of the anterior cruciate ligament in athletes and the incidence of secondary pathology within the knee. J Bone Joint Surg Br. 2010;92(3):362-366.
24.
KogaHMunetaTNagaseT. Comparison of mesenchymal tissues–derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell Tissue Res. 2008;333(2):207-215.
25.
KurosakaMYoshiyaSMizunoTMizunoK.Spontaneous healing of a tear of the anterior cruciate ligament: a report of two cases. J Bone Joint Surg Am. 1998;80(8):1200-1203.
26.
LallierTESpencerA.Use of microarrays to find novel regulators of periodontal ligament fibroblast differentiation. Cell Tissue Res. 2007;327(1):93-109.
27.
LeeBIMinKDChoiHSKimJBKimST.Arthroscopic anterior cruciate ligament reconstruction with the tibial-remnant preserving technique using a hamstring graft. Arthroscopy. 2006;22(3):340.e1-7.
28.
LeeDHNgJChungJWSonnCHLeeKMHanSB.Impact of chronicity of injury on the proportion of mesenchymal stromal cells derived from anterior cruciate ligaments. Cytotherapy. 2014;16(5):586-598.
29.
LiangRWooSLTakakuraYMoonDKJiaFAbramowitchSD.Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: a functional tissue engineering study. J Orthop Res. 2006;24(4):811-819.
30.
LimJKHuiJLiLThambyahAGohJLeeEH.Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy. 2004;20(9):899-910.
31.
LitvinJSelimAHMontgomeryMO. Expression and function of periostin-isoforms in bone. J Cell Biochem. 2004;92(5):1044-1061.
32.
LoIKMarchukLLHartDAFrankCB.Comparison of mRNA levels for matrix molecules in normal and disrupted human anterior cruciate ligaments using reverse transcription-polymerase chain reaction. J Orthop Res. 1998;16(4):421-428.
33.
LohmanderLSOstenbergAEnglundMRoosH.High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum. 2004;50(10):3145-3152.
34.
McIlwraithCWFrisbieDDRodkeyWG. Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects. Arthroscopy. 2011;27(11):1552-1561.
35.
MichalitsisSVlychouMMalizosKNThriskosPHantesME.Meniscal and articular cartilage lesions in the anterior cruciate ligament–deficient knee: correlation between time from injury and knee scores. Knee Surg Sports Traumatol Arthrosc. 2015;23(1):232-239.
36.
MolloyTWangYMurrellG.The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33(5):381-394.
37.
MurrayMMFlemingBC.Biology of anterior cruciate ligament injury and repair: Kappa Delta Ann Doner Vaughn Award Paper 2013. J Orthop Res. 2013;31(10):1501-1506.
38.
MurrayMMFlemingBC.Use of a bioactive scaffold to stimulate anterior cruciate ligament healing also minimizes posttraumatic osteoarthritis after surgery. Am J Sports Med. 2013;41(8):1762-1770.
39.
MurrayMMMartinSDMartinTLSpectorM.Histological changes in the human anterior cruciate ligament after rupture. J Bone Joint Surg Am. 2000;82(10):1387-1397.
40.
MusahlVAbramowitchSDGilbertTW. The use of porcine small intestinal submucosa to enhance the healing of the medial collateral ligament—a functional tissue engineering study in rabbits. J Orthop Res. 2004;22(1):214-220.
41.
NakazawaTNakajimaASekiN. Gene expression of periostin in the early stage of fracture healing detected by cDNA microarray analysis. J Orthop Res. 2004;22(3):520-525.
42.
NaraokaTIshibashiYTsudaE. Time-dependent gene expression and immunohistochemical analysis of the injured anterior cruciate ligament. Bone Joint Res. 2012;1(10):238-244.
43.
NeumanPEnglundMKostogiannisIFridenTRoosHDahlbergLE.Prevalence of tibiofemoral osteoarthritis 15 years after nonoperative treatment of anterior cruciate ligament injury: a prospective cohort study. Am J Sports Med. 2008;36(9):1717-1725.
44.
NguyenDTRamwadhdoebeTHvan der HartCPBlankevoortLTakPPvan DijkCN.Intrinsic healing response of the human anterior cruciate ligament: an histological study of reattached ACL remnants. J Orthop Res. 2014;32(2):296-301.
45.
NohmiSYamamotoYMizukamiH. Post injury changes in the properties of mesenchymal stem cells derived from human anterior cruciate ligaments. Int Orthop. 2012;36(7):1515-1522.
46.
NorrisRABorgTKButcherJTBaudinoTABanerjeeIMarkwaldRR.Neonatal and adult cardiovascular pathophysiological remodeling and repair: developmental role of periostin. Ann N Y Acad Sci. 2008;1123:30-40.
47.
NorrisRADamonBMironovV. Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem. 2007;101(3):695-711.
48.
OiestadBEHolmIAuneAK. Knee function and prevalence of knee osteoarthritis after anterior cruciate ligament reconstruction: a prospective study with 10 to 15 years of follow-up. Am J Sports Med. 2010;38(11):2201-2210.
49.
OntsukaKKotobukiYShiraishiH. Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts. Exp Dermatol. 2012;21(5):331-336.
50.
OuyangHWGohJCLeeEH.Use of bone marrow stromal cells for tendon graft-to-bone healing: histological and immunohistochemical studies in a rabbit model. Am J Sports Med. 2004;32(2):321-327.
51.
PudduGMarianiPFerrettiAConteducaF.Chronic anterior laxity of the knee: classification and coding of the results of surgical treatment. Ital J Orthop Traumatol. 1986;12(2):167-178.
52.
RaiMFPatraDSandellLJBrophyRH.Relationship of gene expression in the injured human meniscus to body mass index: a biologic connection between obesity and osteoarthritis. Arthritis Rheumatol. 2014;66(8):2152-2164.
53.
RaiMFPatraDSandellLJBrophyRH.Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. Arthritis Rheum. 2013;65(8):2090-2101.
54.
RoySPatelDKhannaS. Transcriptome-wide analysis of blood vessels laser captured from human skin and chronic wound-edge tissue. Proc Natl Acad Sci U S A. 2007;104(36):14472-14477.
55.
SaetherEEChamberlainCSLeifermanEM. Enhanced medial collateral ligament healing using mesenchymal stem cells: dosage effects on cellular response and cytokine profile. Stem Cell Rev. 2014;10(1):86-96.
56.
SandbergRBalkforsBNilssonBWestlinN.Operative versus non-operative treatment of recent injuries to the ligaments of the knee: a prospective randomized study. J Bone Joint Surg Am. 1987;69(8):1120-1126.
57.
ScapinelliR.Vascular anatomy of the human cruciate ligaments and surrounding structures. Clin Anat. 1997;10(3):151-162.
58.
ShiYShuBYangR. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6(1):120.
59.
WooSLTakakuraYLiangRJiaFMoonDK.Treatment with bioscaffold enhances the the fibril morphology and the collagen composition of healing medial collateral ligament in rabbits. Tissue Eng. 2006;12(1):159-166.
60.
WuBZhaoZLiSSunL.Preservation of remnant attachment improves graft healing in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy. 2013;29(8):1362-1371.
61.
YagiMWongEKKanamoriADebskiREFuFHWooSL.Biomechanical analysis of an anatomic anterior cruciate ligament reconstruction. Am J Sports Med. 2002;30(5):660-666.
62.
ZyskSPRefiorHJ.Operative or conservative treatment of the acutely torn anterior cruciate ligament in middle-aged patients: a follow-up study of 133 patients between the ages of 40 and 59 years. Arch Orthop Trauma Surg. 2000;120(1-2):59-64.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
