scholarly journals Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice

2021 ◽  
Author(s):  
Alexander Kotelsky ◽  
Anissa Elahi ◽  
Nejat Can ◽  
Ashley Proctor ◽  
Sandeep Mannava ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cruciate Ligament ◽  
Weight Bearing ◽  
Acl Injury ◽  
Joint Loading ◽  
Post Injury ◽  
Chondrocyte Death ◽  
Hind Limbs ◽  
Post Traumatic

Objective: The objective of this study is to understand the role of altered in vivo mechanical environments in knee joints post anterior cruciate ligament (ACL)-injury in chondrocyte vulnerability against mechanical stimuli and in the progression of post-traumatic osteoarthritis (PT-OA). Methods: Differential in vivo mechanical environments were induced by unilateral ACL-injury (uni-ACL-I) and bilateral ACL-injury (bi-ACL-I) in 8-week-old female C57BL/6 mice. The gait parameters, the mechano-vulnerability of in situ chondrocytes, Youngs moduli of cartilage extracellular matrix (ECM), and the histological assessment of OA severity (OARSI score) were compared between control and experimental groups at 0~8-weeks post-ACL-injury. Results: We found that bi-ACL-I mice experience higher joint-loading on their both injured limbs, but uni-ACL-I mice balance their joint-loading between injured and uninjured hind limbs resulting in a reduced joint-loading during gait. We also found that at 4- and 8-week post-injury the higher weight-bearing hind limbs (i.e., bi-ACL-I) had the increased area of chondrocyte death induced by impact loading and higher OARSI score than the lower weight-bearing limbs (uni-ACL-I). Additionally, we found that at 8-weeks post-injury the ECM became stiffer in bi-ACL-I joints and softer in uni-ACL-I joints. Conclusions: Our results show that ACL-injured limbs with lower in vivo joint-loading develops PT-OA significantly slower than injured limbs with higher joint-loading during gait. Our data also indicate that articular chondrocytes in severe PT-OA are more fragile from mechanical impacts than chondrocytes in healthy or mild PT-OA. Thus, preserving physiologic joint-loads on injured joints will reduce chondrocyte death post-injury and may delay PT-OA progression.

scholarly journals A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Motoo Saito ◽  
Kohei Nishitani ◽  
Hanako O. Ikeda ◽  
Shigeo Yoshida ◽  
Sachiko Iwai ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Therapeutic Agent ◽  
Articular Chondrocytes ◽  
Cartilage Explants ◽  
Chondrocyte Death ◽  
Post Traumatic ◽  
Promising Therapeutic Agent

AbstractPost-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.

scholarly journals Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression

2018 ◽  
Vol 19 (9) ◽  
pp. 2657 ◽  
Author(s):  
Aimy Sebastian ◽  
Jiun Chang ◽  
Melanie Mendez ◽  
Deepa Murugesh ◽  
Sarah Hatsell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Cruciate Ligament ◽  
Cartilage Damage ◽  
Acl Injury ◽  
The Other ◽  
Knee Joints ◽  
Mouse Strains ◽  
Post Injury ◽  
Post Traumatic

Anterior cruciate ligament (ACL) injuries often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled ACL injury-induced transcriptional changes in knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6J (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right knee joints of the mice were injured using a non-invasive tibial compression injury model and global gene expression was quantified before and at 1-day, 1-week, and 2-weeks post-injury using RNA-seq. Following injury, injured and uninjured joints of STR/ort and injured C57BL/6J joints displayed significant cartilage degeneration while MRL/MpJ had little cartilage damage. Gene expression analysis suggested that prolonged inflammation and elevated catabolic activity in STR/ort injured joints, compared to the other two strains may be responsible for the severe PTOA phenotype observed in this strain. MRL/MpJ had the lowest expression values for several inflammatory cytokines and catabolic enzymes activated in response to ACL injury. Furthermore, we identified several genes highly expressed in MRL/MpJ compared to the other two strains including B4galnt2 and Tpsab1 which may contribute to enhanced healing in the MRL/MpJ. Overall, this study has increased our knowledge of early molecular changes associated with PTOA development.

Regional Variations in Cartilage Mechanics and Composition Suggest a Sensitivity to Changes in Chronic Joint Loading Patterns

2009 ◽  
Author(s):  
Scott L. Bevill ◽  
Thomas P. Andriacchi
Keyword(s):  
Mechanical Properties ◽  
Tibial Plateau ◽  
Cruciate Ligament ◽  
Weight Bearing ◽  
Dynamic Shear Modulus ◽  
Joint Loading ◽  
Test Bed ◽  
Good Test ◽  
Loading Patterns

It has been suggested that variations in cartilage mechanical properties and biochemistry within a joint may be critical in understanding the implications of altered joint kinematics as a pathway to the initiation of knee osteoarthritis (OA) [1]. For example, the kinematic changes resulting from anterior cruciate ligament (ACL) injury have been suggested as a mechanism for the initiation of OA by altering chronic joint loading patterns in a tissue with low adaptation potential [1]. This mechanism would suggest that regions of cartilage subjected to different habitual post-natal mechanical loading might exhibit, among other things, differences in biochemical content and mechanical properties. The tibial plateau offers a good test bed to evaluate this mechanism since peripheral region articular cartilage (covered by the menisci) appears to experience lower contact pressures in vivo during weight-bearing activity than regions of cartilage exposed to cartilage-cartilage contact [2, 3]. Thus, the purpose of this study was to test the hypothesis that there are significant regional differences in cartilage mechanical properties (including dynamic shear modulus, phase shift angle, and equilibrium Young’s Modulus) and biochemistry (including collagen content, sulfated glycosaminoglycan (s-GAG) content, and water content) between the central and peripheral regions of the porcine tibial plateau.

scholarly journals Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression

2018 ◽  
Author(s):  
Aimy Sebastian ◽  
Jiun C. Chang ◽  
Melanie E. Mendez ◽  
Deepa K. Murugesh ◽  
Sarah Hatsell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Cruciate Ligament ◽  
Cartilage Damage ◽  
Acl Injury ◽  
The Other ◽  
Knee Joints ◽  
Mouse Strains ◽  
Post Injury ◽  
Post Traumatic

Injuries to the anterior cruciate ligament (ACL) often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled ACL injury-induced gene expression changes in knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6 (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right knee joints of the mice were injured using a non-invasive tibial compression injury model that closely mimics ACL rupture in humans and global gene expression was quantified before and at 1-day, 1-week, and 2-weeks post-injury using RNA-seq. Following injury, STR/ort displayed severe cartilage degeneration while MRL/MpJ had little cartilage damage. Gene expression analysis suggested that prolonged inflammation and elevated catabolic activity in STR/ort injured joints, compared to the other two strains may be responsible for the severe PTOA phenotype observed in this strain. MRL/MpJ had the lowest expression values for several inflammatory cytokines and catabolic enzymes activated in response to ACL injury. Furthermore, we identified several genes highly expressed in MRL/MpJ compared to the other two strains including B4galnt2 and Tpsab1 which may contribute to enhanced healing in the MRL/MpJ. Overall, this study has increased our knowledge of early molecular changes associated with PTOA development.

Measuring Strain Distributions in the Anterior Cruciate Ligament Using Ultrasound

2010 ◽  
Author(s):  
Amy Cochran ◽  
Yingxin Gao ◽  
Ursula Krotscheck ◽  
Margret Thompson ◽  
James Stouffer ◽  
...  
Keyword(s):  
Anterior Cruciate Ligament ◽  
Cruciate Ligament ◽  
Treatment Strategies ◽  
Acl Injury ◽  
Physiological Factors ◽  
Detailed Understanding ◽  
Prevention And Treatment ◽  
Anterior Cruciate ◽  
Tissue Motion

Optimal prevention and treatment strategies of anterior cruciate ligament (ACL) injury can be realized with a detailed understanding of how physiological factors impact the ACL. A noninvasive, in vivo method that assesses the ACL’s mechanical integrity is needed to help clarify this multi-factorial pathophysiology. We investigated the use of the noninvasive, in vivo technique, ultrasound strain elastography (USE) (1), to distinguish between normal and injured ACLs. USE is used as a diagnostic tool in oncological (2), hepatic (3), and cardiovascular (4) applications. This technique uses ultrasonic RF data to track tissue motion in order to estimate strain within the tissue.

scholarly journals Effects of Anterior Cruciate Ligament Deficiency on Tibiofemoral Cartilage Thickness and Strains in Response to Hopping

2018 ◽  
Vol 47 (1) ◽  
pp. 96-103 ◽  
Author(s):  
E. Grant Sutter ◽  
Betty Liu ◽  
Gangadhar M. Utturkar ◽  
Margaret R. Widmyer ◽  
Charles E. Spritzer ◽  
...  
Keyword(s):  
Cruciate Ligament ◽  
Acl Injury ◽  
Cartilage Thickness ◽  
Intercondylar Notch ◽  
Dynamic Activity ◽  
Acl Deficiency ◽  
Anterior Cruciate ◽  
Acl Deficient ◽  
Deficient Knee

Background: Changes in knee kinematics after anterior cruciate ligament (ACL) injury may alter loading of the cartilage and thus affect its homeostasis, potentially leading to the development of posttraumatic osteoarthritis. However, there are limited in vivo data to characterize local changes in cartilage thickness and strain in response to dynamic activity among patients with ACL deficiency. Purpose/Hypothesis: The purpose was to compare in vivo tibiofemoral cartilage thickness and cartilage strain resulting from dynamic activity between ACL-deficient and intact contralateral knees. It was hypothesized that ACL-deficient knees would show localized reductions in cartilage thickness and elevated cartilage strains. Study Design: Controlled laboratory study. Methods: Magnetic resonance images were obtained before and after single-legged hopping on injured and uninjured knees among 8 patients with unilateral ACL rupture. Three-dimensional models of the bones and articular surfaces were created from the pre- and postactivity scans. The pre- and postactivity models were registered to each other, and cartilage strain (defined as the normalized difference in cartilage thickness pre- and postactivity) was calculated in regions across the tibial plateau, femoral condyles, and femoral cartilage adjacent to the medial intercondylar notch. These measurements were compared between ACL-deficient and intact knees. Differences in cartilage thickness and strain between knees were tested with multiple analysis of variance models with alpha set at P < .05. Results: Compressive strain in the intercondylar notch was elevated in the ACL-deficient knee relative to the uninjured knee. Furthermore, cartilage in the intercondylar notch and adjacent medial tibia was significantly thinner before activity in the ACL-deficient knee versus the intact knee. In these 2 regions, thinning was significantly influenced by time since injury, with patients with more chronic ACL deficiency (>1 year since injury) experiencing greater thinning. Conclusion: Among patients with ACL deficiency, the medial femoral condyle adjacent to the intercondylar notch in the ACL-deficient knee exhibited elevated cartilage strain and loss of cartilage thickness, particularly with longer time from injury. It is hypothesized that these changes may be related to posttraumatic osteoarthritis development. Clinical Relevance: This study suggests that altered mechanical loading is related to localized cartilage thinning after ACL injury.

scholarly journals USE CAUTION WHEN ASSESSING PRE-OPERATIVE LEG LENGTH DISCREPANCY IN PEDIATRIC PATIENTS WITH ANTERIOR CRUCIATE LIGAMENT INJURIES

2020 ◽  
Vol 8 (4_suppl3) ◽  
pp. 2325967120S0028
Author(s):  
Lindsay M. Schlichte ◽  
Peter D. Fabricant ◽  
Christine Goodbody ◽  
Daniel W. Green
Keyword(s):  
Anterior Cruciate Ligament ◽  
Pediatric Patients ◽  
Cruciate Ligament ◽  
Weight Bearing ◽  
Acl Injury ◽  
Leg Length ◽  
Full Extension ◽  
X Ray ◽  
Length Discrepancy ◽  
Anterior Cruciate

Background: Pre- and post-operative standing hip to ankle radiography is critical for monitoring potential post-operative growth arrest and resultant length and angular deformities after pediatric anterior cruciate ligament (ACL) reconstruction. During acquisition of pre-operative standing alignment radiographs, it is possible that patients are lacking full extension, not weight bearing comfortably, or leaning resulting in inaccurate measurements. Purpose: This study aims to assess both pre- and post-operative radiographic measurements to assess if the standing pre-operative x-ray is a accurate and reliable source for baseline measurements. Methods: We retrospectively reviewed prospectively collected pre-operative and first post-operative full-length hip-to-ankle radiographs in a cohort of skeletally immature athletes who presented with an acute ACL injury and underwent subsequent surgical reconstruction. Initially, leg length discrepancy for 25 patients was measured by 3 orthopedic surgeons (top of femoral head to center of tibial plafond). The intraclass correlation was almost perfect (ICC (2,1) = .996) therefore, 1 surgeon measured the remaining 94 radiographs. Measurements for both the injured and uninjured legs were obtained for comparison and surgeons were blinded to the injured side. Results: A total of 119 pediatric patients (mean age 13.4, range 7-14 years) were included (83 males and 36 females). Patient were categorized as either having ≥5mm, ≥10mm, or ≥15mm LLD on pre-operative standing x-ray. Sixty-two patients (52%) were found to have a pre-operative LLD ≥ 5mm. Forty-one (66%) of these patients tore their ACL on the limb measuring shorter. At 6 month post-operative standing x-ray, 35 patients (56%) resolved to ≤5mm LLD. Eighteen patients had a pre-operative LLD of ≥ 10mm. At 6 month post-operative standing x-ray, 13 (72%) patients resolved to ≤5mm LLD. Five patients had a pre-operative LLD of ≥ 15mm. At 6 month post-operative standing x-ray, 4 (80%) resolved ≤5mm. All patients with a pre-operative LLD of ≥ 13mm had sustained an ACL injury on the limb measuring shorter Conclusion: Of the pediatric ACL patients initially presenting with a pre-operative LLD of ≥ 10mm, 72% demonstrated apparent correction of their LLD on their 6 month standing x-ray. This high rate of LLD pre-operatively but not post operatively calls into question the accuracy of pre-operative standing alignment radiographs for patients after an ACL tear. Surgeons and radiology technicians should be aware of injured patients potentially lacking full extension, leaning, or not weight bearing comfortably, and should consider delaying preoperative radiographic length and alignment analysis until after the patient is able to fully straighten the injured knee and weight bear comfortably.

Effects of Quadriceps and Hamstrings Ratio on ACL Strain During Landing Activities

2012 ◽  
Author(s):  
Carmen E. Quatman ◽  
Ata M. Kiapour ◽  
Ali Kiapour ◽  
Jason W. Levine ◽  
Samuel C. Wordeman ◽  
...  
Keyword(s):  
Knee Joint ◽  
Cruciate Ligament ◽  
Acl Injury ◽  
The United States ◽  
Implant Design ◽  
Reconstruction Technique ◽  
Fe Model ◽  
Acl Injuries

Over 100,000 anterior cruciate ligament (ACL) injuries occur annually in the United States [1]. Of these, 70% are classified as non-contact, many of which occur subsequent to a landing from a jump [2]. While most agree that quadriceps (Q) and hamstrings (H) have a significant contribution in knee biomechanics, the role of quadriceps and hamstrings muscle loads and their ratio (Q/H) in ACL injury remains controversial. Understanding muscle recruitment in high risk activities may improve our knowledge of ACL injury mechanisms. Such insight may improve current prevention strategies to decrease the risk of ACL injury and damage to secondary anatomical structures, all of which may in turn minimize associated posttraumatic knee osteoarthritis. As in vivo quantification of muscle loads remains challenging, especially under dynamic conditions, validated finite element (FE) models of the knee can be used to characterize the role of muscle loads in ACL injury. FE analysis has provided considerable insight into knee joint biomechanics, including ligament function, ligament reconstruction technique and implant design. This study utilized a validated FE model of the knee joint to study the effects of quadriceps to hamstrings ratio (Q/H) on ACL strain during a simulated landing from a jump. We hypothesized that both the ratio and magnitude of muscle loads are critical determinants of ACL loading. Further, a threshold may be reached as the magnitude of quadriceps load exceeds hamstrings load.

scholarly journals One-leg rise performance and associated knee kinematics in ACL-deficient and ACL-reconstructed persons 23 years post-injury

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Andrew Strong ◽  
Eva Tengman ◽  
Divya Srinivasan ◽  
Charlotte K. Häger
Keyword(s):  
Cruciate Ligament ◽  
Scientific Evidence ◽  
Knee Kinematics ◽  
Acl Injury ◽  
Cross Sectional Study ◽  
Knee Function ◽  
Post Injury ◽  
Discriminative Ability ◽  
Cross Sectional ◽  
Knee Abduction

Abstract Background Research indicates reduced knee function and stability decades after anterior cruciate ligament (ACL) injury. Assessment requires reliable functional tests that discriminate such outcomes from asymptomatic knees, while providing suitable loading for different populations. The One-leg rise (OLR) test is common in clinics and research but lacks scientific evidence for its implementation. Our cross-sectional study compared performance including knee kinematics of the OLR between ACL-injured persons in the very long term to controls and between legs within these groups, and assessed the within-session reliability of the kinematics. Methods Seventy ACL-injured individuals (mean age 46.9 ± 5.4 years) treated with either reconstructive surgery and physiotherapy (ACLR; n = 33) or physiotherapy alone (ACLPT; n = 37), on average 23 years post-injury, and 33 age- and sex-matched controls (CTRL) attempted the OLR. Participants completed as many repetitions as possible to a maximum of 50 while recorded by motion capture. We compared between all groups and between legs within groups for total repetitions and decomposed the OLR into movement phases to compare phase completion times, maximum and range of knee abduction and adduction angles, and mediolateral knee control in up to 10 repetitions per participant. Results ACLPT performed significantly fewer OLR repetitions with their injured leg compared to the CTRL non-dominant leg (medians 15 and 32, respectively) and showed significantly greater knee abduction than ACLR and CTRL (average 2.56°-3.69° depending on phase and leg). Distribution of repetitions differed between groups, revealing 59% of ACLPT unable to complete more than 20 repetitions on their injured leg compared to 33% ACLR and 36% CTRL for their injured and non-dominant leg, respectively. Within-session reliability of all kinematic variables for all groups and legs was high (ICC 3,10 0.97–1.00, 95% CI 0.95–1.00, SEM 0.93–1.95°). Conclusions Negative outcomes of OLR performance, particularly among ACLPT, confirm the need to address aberrant knee function and stability even decades post-ACL injury. Knee kinematics derived from the OLR were reliable for asymptomatic and ACL-injured knees. Development of the OLR protocol and analysis methods may improve its discriminative ability in identifying reduced knee function and stability among a range of clinical populations.

scholarly journals Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis

2019 ◽  
Vol 6 (4) ◽  
pp. 211-219
Author(s):  
Derek T Holyoak ◽  
Tibra A Wheeler ◽  
Marjolein C H van der Meulen ◽  
Ankur Singh
Keyword(s):  
Knee Joint ◽  
Joint Damage ◽  
Mechanical Trauma ◽  
Protective Effects ◽  
Post Injury ◽  
On Demand ◽  
Post Traumatic ◽  
Anti Inflammatory

Abstract Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a ‘mechanical pillow’ to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model.

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