Risk Of Anterior Cruciate Ligament Rupture Research Articles

Evaluation of increased posterior tibial slope as a risk factor for anterior cruciate ligament injury

Individuals who sustain anterior cruciate ligament (ACL) injury have an increased risk of developing early onset post traumatic osteoarthritis of the knee despite treatment received [1]. An increase in the posterior tibial slope is postulated to increase the risk of ACL rupture [2]. Measurement of the posterior tibial slope in individuals would serve as a means of screening and identifying those at increased risk of developing ACL injuries to take measures towards prevention. The aim was to measure and compare the mean value of the posterior tibial slope in adult patients with or without ACL injury. This was a hospital-based case-control study comprising 80 patients divided into two matched groups. Posterior tibial slope was measured on the plain lateral radiograph of the knee using the proximal tibial anatomic axis measurement protocol in all participants. Independent sample t-test was used to compare the means of the measured posterior tibial lope between cases and controls. The difference in the measured mean posterior tibial slope between the ACL injured group and the non-ACL injured group was found to be statistically significant with those in the ACL injured group having higher mean values (12.71 ± 1.2° vs 10.25 ± 1.1°) with a P value of < 0.001. Individuals with ACL injury have a significantly greater posterior tibial slope than those without ACL injury when measured on the lateral plain radiograph of the knee using the proximal tibial anatomic axis measurement protocol.

Vertical Stenosis as a Morphological Risk Factor for Anterior Cruciate Ligament Ruptures in Children: A Magnetic Resonance Imaging–Based Comparison

Background: There are known anatomic variations that may lead to traumatic disruption of the anterior cruciate ligament (ACL) identified within adult and adolescent patients. Purpose/Hypothesis: The purpose of this study was to compare the parameters of pediatric knees diagnosed with and without an ACL injury by magnetic resonance imaging. The hypothesis was that children with ACL abnormalities would demonstrate an equivalent notch width index (NWI), but a larger notch height index (NHI), in comparison with age-matched patients without ACL abnormalities, suggesting an association with congenital morphology. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A retrospective comparison cohort study of pediatric knees was performed by evaluating those with a confirmed ACL rupture/deficiency and those with a benign diagnosis on magnetic resonance imaging. Overall, 6 osseous and cartilaginous measurements and 3 ratios (2 newly described) were determined. They were then grouped for statistical purposes by age: children aged 5 to 11 years and adolescents aged 12 to 19 years. Results: A total of 119 (49 children) consecutive patients with an ACL injury and 139 (72 children) healthy patients met inclusion criteria. The interaction between ACL status and age was significant for condylar measurements (P≤ .001), tibial spine height (P = .003), vertical space above tibial spine (P≤ .001), and NWI (P≤ .001) by 2-way analysis of variance. Although the NHI (P < 0.001) and tibial spine prominence (P = 0.039) demonstrated stenosis in the adolescent group, they did not have significant interactions with age and ACL status (P > 0.05). Regarding the transcondylar width, only the children's group had a significant difference regarding ACL status (P < .001), and the mean values in the children's group with ACL tears were nearly identical to those in the adolescent group both with and without ACL tears. The children's group with ACL tears also had a significantly larger tibial spine height compared with healthy children (P < .001). Conclusion: Children, similar to adolescents, demonstrated the effect of the NWI on the risk of ACL tears, but only the adolescent group demonstrated stenosis with the NHI. The morphology of the knee in a child at risk for ACL rupture was not the same as that of an adolescent when considering all dimensions, but it did seem that it was more adolescent-like than child-like at the time of an ACL rupture, refuting the idea of congenital hypoplasia as a common cause.

Identification of genetic variants associated with anterior cruciate ligament rupture and AKC standard coat color in the Labrador Retriever

Canine anterior cruciate ligament (ACL) rupture is a common complex disease. Prevalence of ACL rupture is breed dependent. In an epidemiological study, yellow coat color was associated with increased risk of ACL rupture in the Labrador Retriever. ACL rupture risk variants may be linked to coat color through genetic selection or through linkage with coat color genes. To investigate these associations, Labrador Retrievers were phenotyped as ACL rupture case or controls and for coat color and were single nucleotide polymorphism (SNP) genotyped. After filtering, ~ 697 K SNPs were analyzed using GEMMA and mvBIMBAM for multivariate association. Functional annotation clustering analysis with DAVID was performed on candidate genes. A large 8 Mb region on chromosome 5 that included ACSF3, as well as 32 additional SNPs, met genome-wide significance at P < 6.07E-7 or Log10(BF) = 3.0 for GEMMA and mvBIMBAM, respectively. On chromosome 23, SNPs were located within or near PCCB and MSL2. On chromosome 30, a SNP was located within IGDCC3. SNPs associated with coat color were also located within ADAM9, FAM109B, SULT1C4, RTDR1, BCR, and RGS7. DZIP1L was associated with ACL rupture. Several significant SNPs on chromosomes 2, 3, 7, 24, and 26 were located within uncharacterized regions or long non-coding RNA sequences. This study validates associations with the previous ACL rupture candidate genes ACSF3 and DZIP1L and identifies novel candidate genes. These variants could act as targets for treatment or as factors in disease prediction modeling. The study highlighted the importance of regulatory SNPs in the disease, as several significant SNPs were located within non-coding regions.

MMP3 single-nucleotide polymorphisms are associated with noncontact ACL injuries in competing high-level athletes.

Matrix metalloproteinases (MMPs) play an important role in matrix remodeling, as well as in ligament integrity. Anterior cruciate ligament (ACL) rupture is a severe and frequent knee injury in sports. The aim of this study was to investigate polymorphisms within the MMP3 gene with the predisposition for noncontact ACL rupture in the Croatian professional athletes. One hundred eighty-seven (95 with ACL rupture occurring through a noncontact mechanism and 92 asymptomatic controls) unrelated Caucasians were recruited between 2016 and 2017. All participants were genotyped for three single-nucleotide polymorphisms (SNP) within the MMP3 gene: rs591058 C/T, rs650108 A/G, and rs679620 G/A using the pyrosequencing method. For all three investigated SNPs, genotype frequencies have significantly differed between cases and controls. The MMP3 rs591058 TT (p = 0.0012, odds ratio [OR] = 38.541, 95% confidence interval [CI] = 1.7024-8.7254), rs650108 GG (p = 0.0051, OR = 23.338, 95% CI = 1.2899-4.2226) and rs679620 AA (p = 0.0030, OR = 34.750, 95% CI = 1.5266-7.9101) genotypes, as well as haplotype variant T-G-A (p = 0.0104, OR = 1.71, 95% CI = 1.13-2.59) were significantly overrepresented in cases compared to controls. These results support association between functional variants within the MMP3 gene and the risk of ACL rupture. Still, further research is needed to corroborate these results in a larger population.

Does playing surface affect the risk of anterior cruciate ligament injuries in the National Football League? A look at the 2017 - 2021 NFL seasons

ABSTRACT Background Anterior cruciate ligament (ACL) injuries are devastating injuries for athletes. Prior studies have shown increased ACL injury rates on non-natural surfaces versus natural grass in several sports. The purpose of this study is to calculate the prevalence of ACL injuries in the NFL on natural versus non-natural surfaces to determine if there is a significant increase on non-natural surfaces. Methods Accessing publicly available data for NFL seasons beginning with the 2017–2018 season through 2021–2022 seasons, all ACL injuries with publicly available data concerning timing and playing surface were recorded and categorized according to playing surface. Practice injuries or those without an identifiable playing surface were excluded. Incidence rates, defined as ACL ruptures per game, were calculated. ACL injuries were recorded for each playing surface, as well as the combined category of non-natural grass surface. Odds ratio was calculated to compare the risk of ACL rupture on non-natural surfaces vs natural grass. Results During the 2017–2021 NFL seasons, 173 ACL ruptures were identified with known surfaces. Injury rate for non-natural surfaces was 0.134 compared to 0.097 for grass. Injury rate ratio for non-natural vs natural grass surfaces was 1.211, a 21.1% increased risk of ACL injury in the NFL on non-natural surfaces vs natural grass. OR for non-natural surfaces 1.239 (95% CI 0.900–1.704). Based on these findings there is a trend toward increased risk of ACL injury on non natural grass surfaces, however this did not reach statistical significance. Conclusion Numerous published studies show trends toward increasing rates of ACL injuries on non-natural playing surfaces vs natural grass. Based on our findings the difference is not statistically significant, however it does trend toward increased risk of ACL injury with non-natural surfaces. Further studies should be performed with larger sample sizes in order to further determine the risk of non-natural surfaces.

Application of an in silico approach identifies a genetic locus within ITGB2, and its interactions with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk

ABSTRACT We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. All known human genes were assessed through the model to identify potential new risk genes for anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritised and explored in a case–control study comparing participants with ACL ruptures (ACL-R), including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured control individuals (CON). After gene filtering, 3376 genes, including 411 genes identified through previous whole exome sequencing, were found to be potentially linked to AT and ACL ruptures. Four variants were prioritised: HSPG2:rs2291826A/G, HSPG2:rs2291827G/A, ITGB2:rs2230528C/T and FGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON group compared to ACL-R (p < 0.001) and ACL-NON (p < 0.001) and the TT genotype and T allele were over-represented in the ACL-R group and ACL-NON compared to CON (p < 0.001) group. Several significant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 and ITGB2:rs2230528) and (ITGB2:rs2230528 and FGF9:rs2297429). This study substantiates the efficiency of using a prior knowledge-driven in silico approach to identify candidate genes linked to tendon and ACL injuries. Our biomedical knowledge graph identified and, with further testing, highlighted novel associations of the ITGB2 gene which has not been explored in a genetic case control association study, with ACL rupture risk. We thus recommend a multistep approach including bioinformatics in conjunction with next generation sequencing technology to improve the discovery potential of genomics technologies in musculoskeletal soft tissue injuries. Highlights A biomedical knowledge graph was modelled for musculoskeletal soft tissue injuries to efficiently identify candidate genes for genetic susceptibility analyses. The biomedical knowledge graph and sequencing data identified potential biologically relevant variants to explore susceptibility to common tendon and ligament injuries. Specifically genetic variants within the ITGB2 and FGF9 genes were associated with ACL risk. Novel allele combinations (HSPG2-ITGB2 and ITGB2-FGF9) showcase the potential effect of ITGB2 in influencing risk of ACL rupture.

Knee anatomic geometry accurately predicts risk of anterior cruciate ligament rupture.

Certain anatomical characteristics of the knee have potential relationships with the risk of anterior cruciate ligament (ACL) rupture. There remains a need for stronger evidence using arthroscopy as well as radiological imaging to accurately clarify these relationships. To compare the anatomic geometry of the knee joint between patients with and without ACL ruptures. Case-controlled study of patients with arthroscopically confirmed ACL ruptures (ACL group) compared to patients with arthroscopically confirmed normal ACLs (control group). Magnetic resonance imaging scans were assessed for a total of 14 quantitative radiological variables including medial and lateral tibial slope angles (bone and cartilage measurements), meniscal height, femoral width, intercondylar notch width and tibial depth. A total of 105 patients were included in the study, 55 in the ACL group and 50 in the control group. There was a significant difference (P < 0.05) of most of the radiological measurements between the two groups. There was also a significant difference (P < 0.05) when comparing the variables between sexes. Multiple logistic regression analysis produced a mathematical model utilizing all the radiological measurements with 92.6% classification accuracy in predicating an ACL rupture with the medial tibial slope angle being the strongest predicator variable (odds ratio = 8.97, P = 0.011). Greater postero-inferior directed slope measurements of bone and cartilage in both the lateral and medial compartments with a narrower intercondylar notch width increase the risk of ACL rupture. Mathematical modelling can accurately predict the risk of ACL rupture.

Sex Differences in the Association between Risk of Anterior Cruciate Ligament Rupture and COL5A1 Polymorphisms in Elite Footballers.

Single-nucleotide polymorphisms (SNPs) in collagen genes are predisposing factors for anterior cruciate ligament (ACL) rupture. Although these events are more frequent in females, the sex-specific risk of reported SNPs has not been evaluated. We aimed to assess the sex-specific risk of historic non-contact ACL rupture considering candidate SNPs in genes previously associated with muscle, tendon, ligament and ACL injury in elite footballers. This was a cohort genetic association study. Forty-six (twenty-four females) footballers playing for the first team of FC Barcelona (Spain) during the 2020-21 season were included in the study. We evaluated the association between a history of non-contact ACL rupture before July 2022 and 108 selected SNPs, stratified by sex. SNPs with nominally significant associations in one sex were then tested for their interactions with sex on ACL. Seven female (29%) and one male (4%) participants had experienced non-contact ACL rupture during their professional football career before the last date of observation. We found a significant association between the rs13946 C/C genotype and ACL injury in women footballers (p = 0.017). No significant associations were found in male footballers. The interaction between rs13946 and sex was significant (p = 0.027). We found that the C-allele of rs13946 was exclusive to one haplotype of five SNPs spanning COL5A1. The present study suggests the role of SNPs in genes encoding for collagens as female risk factors for ACL injury in football players. The genetic profiling of athletes at high risk of ACL rupture can contribute to sex-specific strategies for injury prevention in footballers.

Evidence for isokinetic and functional testing in return to sport decisions following ACL surgery.

The rupture and reconstruction of the anterior cruciate ligament (ACL) of the knee are associated with an increased risk of functional instability, a reduction in sports performance, and a higher risk of future additional injuries. Competitive athletes who participate in sports that require pivoting, cutting, and jumping are at particularly high risk for ACL rupture. The return to sport progression continuum after surgery includes sports-specific rehabilitation, evaluation of strength and function, gradual participation in exercise training with progressively challenging activities in the field of play, participation in sports at a lower level, and finally a return to preinjury-level sports competition. This narrative review evaluates the evidence that supports the use of quadriceps and hamstrings isokinetic strength testing and sports-specific functional skills assessments to evaluate progress with rehabilitation after ACL surgery. Strength evaluations, hop tests, agility tests, and the limb symmetry index are described, as well as the associations of quadriceps and hamstrings muscle strength and functional test results with successful return to sports and the risk of ACL graft rupture and contralateral knee injuries. Suggestions for future research directions are presented including the importance of presurgery testing, standardization of test batteries, and comparison of test results with normative data.

The Relationship Between Lateral Femoral Condyle Index and Noncontact Anterior Cruciate Ligament Rupture.

PurposeThe purpose of this study was to examine the relationship between distal femoral morphology and noncontact anterior cruciate ligament (ACL) rupture and the differences between digital X-ray imaging systems (DR) and magnetic resonance imaging (MRI) to evaluate distal femoral morphology.MethodsA retrospective case-control study was performed on 120 patients. Two age- and sex-matched cohorts (each n = 60) were analyzed: primary ACL ruptures and a control group consisting of isolated meniscal tears. The lateral femoral condyle index (LFCI) was measured by DR and by MRI to quantify femoral sphericity. Differences among two groups were compared, and diagnostic performance of the risk factors was assessed. In addition, differences between DR and MRI to evaluate LFCI were examined.ResultsThe LFCI by MRI was smaller in the knees with primary ACL rupture (median, 0.71; range, 0.62–0.78) than that of the control group (median, 0.77; range, 0.66–0.85) (p < 0.01). The LFCI was also significantly smaller in the knees with primary ACL rupture (median, 0.72; range, 0.63–0.77) than that of the control group (median, 0.79; range, 0.65–0.84) (p < 0.01) by DR. A cutoff of 0.74 of MRI yielded a sensitivity of 77% and a specificity of 78% to predict an ACL rupture, and of 0.75 of DR yield a sensitivity of 87% and a specificity of 77% to predict an ACL rupture.ConclusionThis study showed that a decreased LFCI is associated with an ACL rupture, and both DR and MRI measurements can effectively predict the risk of ACL rupture. This helps expand the scope of the application of the LFCI and helps clinicians identify susceptible individuals who may benefit from targeted ACL rupture prevention counseling and intervention.

K-Space Data Reconstruction Algorithm-Based MRI Diagnosis and Influencing Factors of Knee Anterior Cruciate Ligament Injury.

This study was aimed at investigating the diagnostic value of MRI based on K-space data reconstruction algorithm for anterior cruciate ligament (ACL) injury of knee joint and the influencing factors of ligament injury. 96 patients with ACL injury of knee joint were selected, and they were randomly divided into two groups: group A (arthroscopy) and group B (MRI examination), and another 96 healthy volunteers in the same period were selected as the control group. The test results of each indicator were compared. The results showed that the signal-to-noise ratio (SNR) of SMASH algorithm was higher than that of sum of squares (SOS) algorithm. In group A, there were 66 positive and 30 negative tests, and in group B, there were 56 positive and 40 negative tests (P < 0.05). The intercondylar fossa width, the intercondylar fossa width index, and the ratio of tibial intercondylar eminence width to intercondylar fossa width in group B were lower than those in the control group (P < 0.05). Compared with the traditional SOS algorithm, SMASH algorithm can improve the image quality, reduce the impact of damage data on the final synthesis image, and improve the image SNR. In clinical work, the ratio of the width of tibial intercondylar eminence to the width of femoral intercondylar fossa can be measured by imaging data to evaluate the matching between tibial intercondylar eminence and femoral intercondylar fossa, so as to evaluate the risk of ACL rupture.

Genetic variants within the COL5A1 gene are associated with ligament injuries in physically active populations from Australia, South Africa, and Japan

ABSTRACT Previous small-scale studies have shown an association between the COL5A1 gene and anterior cruciate ligament (ACL) injury risk. In this larger study, the genotype and allele frequency distributions of the COL5A1 rs12722 C/T and rs10628678 AGGG/deletion (AGGG/-) indel variants were compared between participants: (i) with ACL injury in independent and combined cohorts from South-Africa (SA) and Australia (AUS) vs controls (CON), and (ii) with any ligament (ALL) or only ACL injury in a Japanese (JPN) cohort vs CON. Samples were collected from SA (235 cases; 232 controls), AUS (362 cases; 80 controls) and JPN (500 cases; 1,403 controls). Genomic DNA was extracted and genotyped. Distributions were compared, and inferred haplotype analyses performed. No independent associations were noted for rs12722 or rs10628678 when the combined SA + AUS cohort was analysed. However, the C-deletion (rs12722-rs10628678) inferred haplotype was under-represented (p = 0.040, OR = 0.15, CI = 0.04-0.56), while the T-deletion inferred haplotype was over-represented in the female SA + AUS ACL participants versus controls (p < 0.001, OR = 4.74, CI = 1.66-13.55). Additionally, the rs12722 C/C genotype was under-represented in JPN CON vs ACL (p = 0.039, OR = 0.52, 0.27-1.00), while the rs10628678 −/− genotype was associated with increased risk of any ligament injuries (p = 0.035, OR = 1.31, CI = 1.02-1.68) in the JPN cohort. Collectively, these results highlight that a region within the COL5A1 3’-UTR is associated with ligament injury risk. This must be evaluated in larger cohorts and its functional relevance to the structure and capacity of ligaments and joint biomechanics be explored. Highlights The COL5A1 T-deletion inferred haplotype (rs12722-rs10628678) was associated with an increased risk of ACL rupture in the combined SA and AUS female participants. The COL5A1 C-deletion inferred haplotype (rs12722-rs10628678) was associated with a decreased risk of ACL rupture in the combined SA and AUS female participants. The COL5A1 rs12722 C/C and rs10628678 −/− genotypes were associated with increased risk of ACL rupture and of ligament injuries in JPN, respectively. A region within the COL5A1 3’-UTR is associated with risk of ligament injury, including ACL rupture, and therefore the functional significance of this region on ligament capacity and joint biomechanics requires further exploration.

Genetics Variants associated with Anterior Cruciate Ligament injury in Australia, South Africa, and Japan

Previous small-scale studies have shown an association between the COL5A1 gene and anterior cruciate ligament (ACL) injury risk. In this larger study, the genotype and allele frequency distributions of the COL5A1 rs12722 C/T and rs10628678 AGGG/deletion (AGGG/-) indel variants were compared between: i) participants with ACL injury in independent and combined cohorts from South-Africa (SA) and Australia (AUS) vs controls (CON), and ii) participants with any ligament or only ACL injury in a Japanese (JPN) cohort vs CON. Samples were collected from SA (n=467; n=235 cases; n=232 controls), AUS (n=442; n=362 cases; n=80 controls) and JPN (n=1,903; cases n=500; n=1,403 controls). Genomic DNA was extracted and genotyped. Distributions were compared, and inferred haplotype analyses performed. No independent associations were noted for rs12722 or rs10628678 when the combined SA and AUS cohort was analysed. However, the rs12722-rs10628678 C- inferred haplotype was over-represented in the female SA + AUS CON vs ACL (p=0.040, OR=0.15, CI=0.04-0.56), whereas T- inferred haplotype was over-represented in the ACL SA+AUS participants in female participants (p<0.001, OR=4.74, CI=1.66-13.55). Moreover, the rs12722 C/C genotype was over-represented in JPN ACL vs CON (p=0.039, OR=0.52, 0.27-1.00), and the rs10628678 -/- genotype over-represented with increased risk of ligament injuries (p=0.035, OR=1.31, CI=1.02-1.68) in the JPN cohort. Collectively, these results highlight that a region within the COL5A1 3’-UTR is associated with ligament susceptibility. This must be evaluated in larger cohorts and functional contribution to ligament and knee joint biomechanics further explored. Highlights▪The rs12722 rs10628678 T- inferred haplotype was over-represented with increased risk of ACL rupture in the combined SA and AUS female participants.▪The rs12722 rs10628678 C- inferred haplotype was over-represented with decreased risk of ACL rupture in the combined SA and AUS female participants.▪The rs12722 C/C genotype and rs10628678 -/- genotype was associated with increased risk of ACL rupture and ligament injuries in JPN, respectively.▪A region within the COL5A1 3’-UTR is associated with susceptibility to ligament injuries, ACL rupture in particular, and must be investigated further as it may have a bearing on functional capacity of ligaments or joint biomechanics. Conflict of interest statement: My co-authors and I acknowledge that we have no conflict of interest of relevance to the submission of the abstract entitled "COL5A1 Gene variants and ligament injuries in Australian, South African, and Japanese populations" to be presented in the SMA conference in 2021.

Risk modelling further implicates the angiogenesis pathway in anterior cruciate ligament ruptures

ABSTRACT The aim of this study was to explore the interactions between the interleukins and the angiogenesis signalling pathway, following a pathway-based approach. Statistical modelling tools were used to develop a preliminary polygenic risk assessment model for anterior cruciate ligament (ACL) ruptures, incorporating the angiogenesis signalling genes (VEGFA and KDR) and interleukins (IL1B, IL6, IL6R) which also function to regulate angiogenesis. Multivariate logistic regression analysis was used to identify the most informative contributors to ACL rupture risk from a range of eleven potential intrinsic risk factors: age, sex, BMI and eight genetic polymorphisms within five genes, namely, IL1B rs16944 C/T, IL6 rs1800795 G/C, IL6R rs2228145 C/A, VEGFA rs699947 C/A, VEGFA rs1570360 G/A, VEGFA rs2010963 C/G, KDR rs2071559 A/G and KDR rs1870377 T/A. A total of 232 asymptomatic controls (CON) and 234 participants with surgically diagnosed ACL ruptures, of which 135 participants reported a non-contact mechanism of injury (NON subgroup), were previously genotyped for the selected polymorphisms. The polygenic risk model identified the VEGFA rs699947 CC genotype (p = 0.024, odds ratio (OR): 3.35, 95% confidence interval (CI): 1.17–9.62), VEGFA rs2010963 GC genotype (p = 0.049, OR: 2.43, 95% CI: 1.00–5.87), age (p = 0.011, OR: 0.97, 95% CI: 0.95–0.99) and BMI (p = 0.009, OR:1.09, 95% CI: 0.57–2.11) as the most significant predictors of ACL rupture risk from the data included. The results of this study highlight VEGFA, age and BMI as biologically significant components of this network requiring further investigation in the context of musculoskeletal soft tissue injury risk. Highlights The findings of this study highlight the VEGFA gene, age and BMI as biologically significant contributors to ACL rupture susceptibility. Upon further validation of these risk factors, they may be included in genetic risk assessment tools to design pre-habilitation strategies, prescribe appropriate treatment strategies after injury or to assess how an individual is likely to respond to load. Polygenic risk models aid in highlighting the components of the complex ECM remodelling pathway requiring further investigation, using a multidisciplinary approach. VEGFA is a key angiogenic protein contributing to ECM homeostasis and may therefore have potential therapeutic implications that need to be explored.

Long-term Effect of a Single Subcritical Knee Injury: Increasing the Risk of Anterior Cruciate Ligament Rupture and Osteoarthritis

Background: Rupture of the anterior cruciate ligament (ACL) is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA), but patients with the “same injury” can have vastly different trajectories for the onset and progression of disease. Minor subcritical injuries preceding the critical injury event may drive this disparity through preexisting tissue pathologies and sensory changes. Purpose: To investigate the role of subcritical injury on ACL rupture risk and PTOA through the evaluation of pain behaviors, joint mechanics, and tissue structural change in a mouse model of knee injury. Study Design: Controlled laboratory study. Methods: Ten-week-old male C57BL/6J mice were allocated to naïve control and subcritical knee injury groups. Injury was induced by a single mechanical compression to the right hindlimb, and mice were evaluated using joint histopathology, anteroposterior joint biomechanics, pain behaviors (mechanical allodynia and hindlimb weightbearing), and isolated ACL tensile testing to failure at 1, 2, 4, or 8 weeks after injury. Results: Subcritical knee injury produced focal osteochondral lesions in the patellofemoral and lateral tibiofemoral compartments with no resolution for the duration of the study (8 weeks). These lesions were characterized by focal loss of proteoglycan staining, cartilage structural change, chondrocyte pathology, microcracks, and osteocyte cell loss. Injury also resulted in the rapid onset of allodynia (at 1 week), which persisted over time and reduced ACL failure load (P = .006; mean ± SD, 7.91 ± 2.01 N vs 9.37 ± 1.01 N in naïve controls at 8 weeks after injury), accompanied by evidence of ACL remodeling at the femoral enthesis. Conclusion: The present study in mice establishes a direct effect of a single subcritical knee injury on the development of specific joint tissue pathologies (osteochondral lesions and progressive weakening of the ACL) and allodynic sensitization. These findings demonstrate a predisposition for secondary critical injuries (eg, ACL rupture) and an increased risk of PTOA onset and progression (structurally and symptomatically). Clinical Relevance: Subcritical knee injuries are a common occurrence and, based on this study, can cause persistent sensory and structural change. These findings have important implications for the understanding of risk factors of ACL injury and subsequent PTOA, particularly with regard to prevention and management strategies following an often underreported event.

Bayesian and Machine Learning Models for Genomic Prediction of Anterior Cruciate Ligament Rupture in the Canine Model.

Anterior cruciate ligament (ACL) rupture is a common, debilitating condition that leads to early-onset osteoarthritis and reduced quality of human life. ACL rupture is a complex disease with both genetic and environmental risk factors. Characterizing the genetic basis of ACL rupture would provide the ability to identify individuals that have high genetic risk and allow the opportunity for preventative management. Spontaneous ACL rupture is also common in dogs and shows a similar clinical presentation and progression. Thus, the dog has emerged as an excellent genomic model for human ACL rupture. Genome-wide association studies (GWAS) in the dog have identified a number of candidate genetic variants, but research in genomic prediction has been limited. In this analysis, we explore several Bayesian and machine learning models for genomic prediction of ACL rupture in the Labrador Retriever dog. Our work demonstrates the feasibility of predicting ACL rupture from SNPs in the Labrador Retriever model with and without consideration of non-genetic risk factors. Genomic prediction including non-genetic risk factors approached clinical relevance using multiple linear Bayesian and non-linear models. This analysis represents the first steps toward development of a predictive algorithm for ACL rupture in the Labrador Retriever model. Future work may extend this algorithm to other high-risk breeds of dog. The ability to accurately predict individual dogs at high risk for ACL rupture would identify candidates for clinical trials that would benefit both veterinary and human medicine.

Matrix Metalloproteinase Genes (MMP1, MMP10, MMP12) on Chromosome 11q22 and the Risk of Non-Contact Anterior Cruciate Ligament Ruptures.

Background: Sequence variants within the matrix metalloproteinases genes remain plausible biological candidates for further investigation of anterior cruciate ligament (ACL) rupture risk. The aim of the present study was to establish whether variants within the MMP1 (rs1799750, ->G), MMP10 (rs486055, C > T) and MMP12 (rs2276109, T > C) genes were associated with non-contact ACL rupture in a Polish cohort. Methods: The unrelated, self-reported Polish Caucasian participants consisted of 228 (157 male) individuals with primary non-contact ACL rupture and 202 (117 male) participants without any history of ACL rupture. All samples were genotyped in duplicate using the Applied Biosystems TaqMan® methodology. The statistical analyses were involved in determining the distribution of genotype and allele frequencies for the investigated polymorphisms between the diagnostic groups. Furthermore, pseudo-haplotypes were constructed to assess possible gene–gene interactions. Results: All genotype frequencies in the ACL rupture and control groups conformed to Hardy Weinberg Equilibrium expectations. None of the polymorphisms were associated with risk of non-contact ACL rupture under the codominant, dominant, recessive and over-dominant genetic models. Likewise, no genotype–genotype combinations inferred as “haplotypes” as a proxy of gene–gene interactions were associated with the risk of non-contact ACL ruptures. Conclusions: Despite the fact that the current study did not support existing evidence suggesting that variants within the MMP1, MMP10, and MMP12 genes influence non-contact ACL rupture risk, future work should include high-throughput sequencing technologies to identify potential targeted polymorphisms to fully characterize the 11q22 region with susceptibility to non-contact ACL rupture susceptibility in a Polish cohort.

A decreased ratio of height of lateral femoral condyle to anteroposterior diameter is a risk factor for anterior cruciate ligament rupture

BackgroundStudies have shown that the spherical shape of the lateral femoral condyle has a clear relationship with the relative axial movement of tibiofemoral joint and the anterior cruciate ligament (ACL) rupture. The purpose of this study was to describe the distal curvature of the lateral femoral condyle by ratio of height of lateral femoral condyle to anteroposterior diameter (HAPR), and evaluate its correlation with ACL rupture.MethodsA retrospective case-control study of 64 patients was conducted. Two age-and sex-matched cohorts (each n = 32) were analyzed: primary ACL ruptures, and a control group consisting of isolated meniscal tears. On the radiograph, the distance from the intersection of the axis of the distal femur and the anteriorly diameter of the lateral femoral condyle to the lower point of the lateral femoral condyle divided by the anteriorly diameter of the lateral femoral condyle is HAPR. The HAPR was measured by digital radiograph imaging systems (DR) to quantify femoral sphericity. Cutoff values were defined; and diagnostic performance of the risk factors was assessed. Meanwhile, we measured the posterior tibial slope (PTS) on radiograph and compared the two methods to evaluate the significance of HAPR in predicting ACL rupture.ResultsA total of sixty-four patients who met the inclusion criteria were included in the final analysis (32 with primary ACL rupture, 32 controls). The HAPR was smaller in the knees with primary ACL rupture (0.31 ± 0.02) than that of the control group (0.33 ± 0.02) (p < 0.01). The PTS was bigger in the knees with primary ACL rupture (8.18 ± 2.77) than that of the control group (6.61 ± 2.85) (p = 0.036). The AUC of HAPR was bigger (0.825; 95% CI, 0.72–0.93) than that of PTS (0.675; 95%CI, 0.85–0.81). The calculated cutoff of HAPR of 0.32 (Youden index, 0.56) was associated with an increased risk for ACL rupture, with sensitivity of 75% and specificity of 81% to predict an ACL rupture.ConclusionsThis study showed that a decreased HAPR is associated with an ACL rupture, and the decrease of HAPR was more significant in predicting ACL ruptures than the PTS. This helps clinicians identify susceptible individuals who may benefit from targeted ACL rupture prevention counseling and intervention.

Exploring new genetic variants within COL5A1 intron 4-exon 5 region and TGF-β family with risk of anterior cruciate ligament ruptures.

Variants within genes encoding structural and regulatory elements of ligaments have been associated with musculoskeletal soft tissue injury risk. The role of intron 4-exon 5 variants within the α1 chain of type V collagen (COL5A1) gene and genes of the transforming growth factor-β (TGF-β) family, TGFBR3 and TGFBI, was investigated on the risk of anterior cruciate ligament (ACL) ruptures. A case-control genetic association study was performed on 210 control (CON) and 249 participants with surgically diagnosed ruptures (ACL), of which 147 reported a noncontact mechanism of injury (NON). Whole-exome sequencing data were used to prioritize variants of potential functional relevance. Genotyping for COL5A1 (rs3922912 G>A, rs4841926 C>T, and rs3124299 C>T), TGFBR3 (rs1805113 G>A and rs1805117 T>C), and TGFBI (rs1442 G>C) was performed using Taqman SNP genotyping assays. Significant overrepresentation of the G allele of TGFBR3 rs1805113 was observed in CON vs ACL (P = .014) and NON groups (P = .021). Similar results were obtained in a female with the G allele (CON vs ACL: P = .029; CON vs NON: P = .016). The TGFBI rs1442 CC genotype was overrepresented in the female ACL vs CON (P = .013). Associations of inferred allele combinations were observed in line with the above results. COL5A1 intron 4-exon 5 genomic interval was not associated with the risk of ACL ruptures. Instead, this novel study is the first to use this approach to identify variants within the TGF-β signaling pathway to be implicated in the risk of ACL ruptures. A genetic susceptibility interval was identified to be explored in the context of extracellular matrix remodeling.

Contralateral and siblings' knees are at higher risk of ACL tear for patients with a positive history of ACL tear.

Recent studies have shown that several genetic factors can cause susceptibility to anterior cruciate ligament (ACL) rupture. The aim of the present study was to evaluate certain underlying factors that increase the risk of ACL rupture. Eight hundred thirty-six patients with ACL rupture who underwent ACL reconstructive surgery from 2010 to 2013 at an academic center completed a minimum of 5years post-operation follow-up. The collected variables included sex, age, height, weight, exercise level, time interval between ACL rupture in the first knee and contralateral ACL rupture, dominant leg, side of the involved knee and sibling history of ACL rupture. The median follow-up duration was 6.5 (range: 5-8) years. Eighty-three patients (9.9%) had a contralateral ACL rupture, and 155 patients (18.5%) had siblings with a history of ACL rupture. The rate of contralateral ACL rupture was three times higher in women than in men and in patients with siblings with a history of ACL rupture than in those without such history. In addition, the risk of contralateral ACL rupture was higher in those younger than 30years of age, those with a BMI of 20-25kg/m2 and those who participated in regular sports activity. However, whether the involved knee was on the dominant or nondominant side had no effect on the incidence of contralateral ACL rupture. The results of the study showed that 69 (83.1%) of the contralateral ACL ruptures occurred within the first 2years after the primary operation. In a 5- to 8-year follow-up, one out of every ten patients had a contralateral ACL rupture, and two out of every ten patients had siblings with a history of ACL rupture. The findings suggest that having a sibling with a history of ACL rupture and being female are important risk factors for ACL rupture of the contralateral knee. III.