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Collagen XII Deficiency Increases the Risk of Anterior Cruciate Ligament Injury in Mice.

ABSTRACT: Anterior cruciate ligament (ACL) rupture is a common knee injury for athletes. Although surgical reconstruction is recommended for the treatment of ACL ruptures, 100% functional recovery is unlikely. Therefore, the discovery of risk factors for ACL ruptures may prevent injury. Several studies have reported an association between polymorphisms of the collagen XII gene COL12A1 and ACL rupture. Collagen XII is highly expressed in tendons and ligaments and regulates tissue structure and mechanical property. Therefore, we hypothesized that collagen XII deficiency may cause ACL injury. To elucidate the influence of collagen XII deficiency on ACL, we analyzed a mouse model deficient for Col12a1. Four- to 19-week-old male Col12a1^-/- and wild-type control mice were used for gait analysis; histological and immunofluorescent analysis of collagen XII, and real-time RT-PCR evaluation of Col12a1 mRNA expression. The Col12a1^-/- mice showed an abnormal gait with an approximately 2.7-fold increase in step angle, suggesting altered step alignment. Col12a1^-/- mice displayed 20-60% ACL discontinuities, but 0% discontinuity in the posterior cruciate ligament. No discontinuities in knee ligaments were found in wild-type mice. Collagen XII mRNA expression in the ACL tended to decrease with aging. Our study demonstrates for the first time that collagen XII deficiency increases the risk of ACL injury.

SUBMITTER: Fukusato S

PROVIDER: S-EPMC8467728 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:With the increasing number of individuals participating in sports every year, injury - specifically anterior cruciate ligament (ACL) injury - remains an inherent risk factor for participants. The majority of ACL injuries occur from a non-contact mechanism, and there is a high physical and financial burden associated with injury. Understanding the risk factors for ACL injury may aid in the development of prevention efforts. Purpose:The purpose of this review was to synthesize and appraise existing literature for risk factors associated with non-contact anterior cruciate ligament (ACL) injury in both sexes. Study Design:Systematic review. Methods:An electronic literature search was conducted utilizing the MEDLINE database and The Cochrane library for articles available through February 2016. All titles and abstracts were reviewed and full text articles meeting eligibility criteria were assessed in detail to determine inclusion or exclusion. Articles reviewed in full text were reviewed for scientific evidence of risk factors for ACL injury. Results from studies were extracted and initially classified as either intrinsic or extrinsic risk factors, and then further categorized based upon the evidence presented in the studies meeting inclusion criteria. Data extracted from eligible studies included general study characteristics (study design, sample characteristics), methodology, and results for risk factors included. Results:Principal findings of this systematic review identified the following risk factors for ACL injury in both sexes: degrading weather conditions, decreased intercondylar notch index or width, increased lateral or posterior tibial plateau slope, decreased core and hip strength, and potential genetic influence. Conclusions:Neuromuscular and biomechanical risk factors may be addressed through neuromuscular preventative training programs. Though some extrinsic and other inherent physiological factors tend to be non-modifiable, attempts to improve upon those modifiable factors may lead to a decreased incidence of ACL injury. Level of Evidence:2a.

Project description:PurposeCertain types of repetitive sub-maximal knee loading cause microfatigue damage in the human anterior cruciate ligament (ACL) that can accumulate to produce macroscopic tissue failure. However, monitoring the progression of that ACL microfatigue damage as a function of loading cycles has not been reported. To explore the fatigue process, a confocal laser endomicroscope (CLEM) was employed to capture sub-micron resolution fluorescence images of the tissue in situ. The goal of this study was to quantify the in situ changes in ACL autofluorescence (AF) signal intensity and collagen microstructure as a function of the number of loading cycles.MethodsThree paired and four single cadaveric knees were subjected to a repeated 4 times bodyweight landing maneuver known to strain the ACL. The paired knees were used to compare the development of ACL microfatigue damage on the loaded knee after 100 consecutive loading cycles, relative to the contralateral unloaded control knee, through second harmonic generation (SHG) and AF imaging using confocal microscopy (CM). The four single knees were used for monitoring progressive ACL microfatigue damage development by AF imaging using CLEM.ResultsThe loaded knees from each pair exhibited a statistically significant increase in AF signal intensity and decrease in SHG signal intensity as compared to the contralateral control knees. Additionally, the anisotropy of the collagen fibers in the loaded knees increased as indicated by the reduced coherency coefficient. Two out of the four single knee ACLs failed during fatigue loading, and they exhibited an order of magnitude higher increase in autofluorescence intensity per loading cycle as compared to the intact knees. Of the three regions of the ACL - proximal, midsubstance and distal - the proximal region of ACL fibers exhibited the highest AF intensity change and anisotropy of fibers.ConclusionsCLEM can capture changes in ACL AF and collagen microstructures in situ during and after microfatigue damage development. Results suggest a large increase in AF may occur in the final few cycles immediately prior to or at failure, representing a greater plastic deformation of the tissue. This reinforces the argument that existing microfatigue damage can accumulate to induce bulk mechanical failure in ACL injuries. The variation in fiber organization changes in the ACL regions with application of load is consistent with the known differences in loading distribution at the ACL femoral enthesis.

Project description:BackgroundKnee joint geometry has been associated with risk of suffering an anterior cruciate ligament (ACL) injury; however, few studies have utilized multivariate analysis to investigate how different aspects of knee joint geometry combine to influence ACL injury risk.HypothesesCombinations of knee geometry measurements are more highly associated with the risk of suffering a noncontact ACL injury than individual measurements, and the most predictive combinations of measurements are different for males and females.Study designCase-control study; Level of evidence, 3.MethodsA total of 88 first-time, noncontact, grade III ACL-injured subjects and 88 uninjured matched-control subjects were recruited, and magnetic resonance imaging data were acquired. The geometry of the tibial plateau subchondral bone, articular cartilage, and meniscus; geometry of the tibial spines; and size of the femoral intercondylar notch and ACL were measured. Multivariate conditional logistic regression was used to develop risk models for ACL injury in females and males separately.ResultsFor females, the best fitting model included width of the femoral notch at its anterior outlet and the posterior-inferior-directed slope of the lateral compartment articular cartilage surface, where a millimeter decrease in notch width and a degree increase in slope were independently associated with a 50% and 32% increase in risk of ACL injury, respectively. For males, a model that included ACL volume and the lateral compartment posterior meniscus to subchondral bone wedge angle was most highly associated with risk of ACL injury, where a 0.1 cm3 decrease in ACL volume (approximately 8% of the mean value) and a degree decrease in meniscus wedge angle were independently associated with a 43% and 23% increase in risk, correspondingly.ConclusionCombinations of knee joint geometry measurements provided more information about the risk of noncontact ACL injury than individual measures, and the aspects of geometry that best explained the relationship between knee geometry and the risk of injury were different between males and females. Consequently, a female with both a decreased femoral notch width and an increased posterior-inferior-directed lateral compartment tibial articular cartilage slope combined or a male with a decreased ACL volume and decreased lateral compartment posterior meniscus angle were most at risk for sustaining an ACL injury.

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Collagen XII Deficiency Increases the Risk of Anterior Cruciate Ligament Injury in Mice.

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