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1. Targeted delivery of miR125a-5p and human Factor VIII attenuates molecular mediators of hemophilic arthropathy.

Author

Senthilkumar, Mohankumar B., Sarangi, Pratiksha, Amit, Sonal, Senguttuvan, Senthilnathan, Kumar, Narendra, and Jayandharan, Giridhara R.

Subjects
*BLOOD coagulation factor VIII, *JOINT diseases, *CHARCOT joints, *MATRIX metalloproteinases, *HEMOPHILIACS, *ADENO-associated virus
Abstract

Hemophilic arthropathy (HA) due to repeated bleeding into the joint cavity is a major cause of morbidity in patients with hemophilia. The molecular mechanisms contributing to this condition are not well characterized. MicroRNAs (miRs) are known to modulate the phenotype of multiple joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Since miR125a is known to modulate disease progression in OA and RA, we performed a targeted screen of miR125a-5p and its target genes in a murine model of chronic HA. A digital PCR analysis demonstrated significant downregulation of miR125a-5p (2-fold vs control joint). Further molecular evaluation revealed elevated expression of the immunological markers STAT1 (7.6-fold vs control joint) and TRAF6 (10.6 fold vs control joint), which are direct targets of miR125a-5p. We then studied the impact of targeted overexpression of miR125a-5p using an Adeno-associated virus (AAV) vector in modulating the molecular mediators of HA. AAV5-miR125a vectors were administered intra-articularly either alone or in combination with a low dose of AAV8-based human factor 8 (F8) gene in a murine model of HA. We observed significantly increased expression of miR125a-5p in AAV5-miR125a administered mice (~12 fold vs injured joint) or in combination with AAV8-F8 vectors (~44 fold vs injured joint). The activity assay revealed ~17 %–20 % FVIII levels in mice that received low dose liver-directed F8 gene therapy. Further immunohistochemical analysis, demonstrated a decrease in inflammatory markers (STAT1 and TRAF6) and cartilage-degrading matrix metalloproteinases (MMPs) 3, 9, 13 in the joints of treated animals. These data highlight the crucial role of miR125a-5p in the development of HA. Targeted profiling and validation by AAV based miR125a delivery identifies the role of miR125a-5p-TRAF6- STAT1 axis, in the sustenance of inflammatory pathophysiology in a chronic hemophilic arthropathy model. Created using Biorender.com. [Display omitted] • miR125a-5p is a potential molecular mediator of hemophilic arthropathy • The molecular mediators, STAT1 and TRAF6, the direct targets of miR125a-5p, regulates MMP activity in the arthritic joints. • AAV based miR125a-5p and F8 vectors alleviates the pathogenesis of HA by downregulation of MMPs 3, 9 and 13. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Evaluation radiologischer Risikofaktoren und deren Einfluss auf die Arthroseentwicklung und das Reluxationsrisiko bei patellofemoraler Instabilität

Author

Bartner, Philipp Christoph Lukas

Subjects
patellofemoral osteoarthritis, APIF, patellofemoral instability, recurrent lateral patellar dislocation risk, cartilage deterioration, lateral patellar dislocation, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Abstract

Einleitung: Die Risikofaktoren der patellofemoralen Instabilität (PFI) und Patellaluxationen sind bekannt. Welche Faktoren einzeln oder in Kombination einen direkten Einfluss auf die patellofemorale Arthroseentwicklung (pFA) und das Reluxationsrisiko haben, soll überprüft werden. Material und Methoden: Eine Datenbank mit Patienten mit PFI wurde erstellt. Patienten mit mindestens einmaliger Patellaluxation, vollständiger Krankengeschichte und MRT-Untersuchung vor operativen Interventionen bezüglich der patellofemoralen Erkrankungen wurden in diese Datenbank aufgenommen und die Risikofaktoren (APFIs) Patellaposition (ISI, CDI), Trochleadysplasie (Dejour-Klassifikation), TTTG, TT-PCL, PT-PCL, Sulkuswinkel und laterale Trochleainklination vermessen und analysiert (n = 300). Bei vorliegender Ganzbeinaufnahme (n = 96) und Rotations-MRT (n = 123) wurde zusätzlich die Beinachse (MAD, HKA, mLDFW, MPTW) und Rotation (Antetorsionswinkel nach Waidelich und modifizierter Methode nach Jarrett, Tibiatorsion, Knieversion) untersucht. Die Korrelationen zwischen APIFs mit pfA und der Einfluss des Alters und der Luxationsanzahl wurden überprüft. Zur Bewertung des Knorpelstatus mindestens 15 Jahre nach Erstluxation wurde die gesamte Studienpopulation gefiltert und eine Follow-up-Gruppe gebildet (n = 49). Die Beziehung zwischen APIFs und dem Reluxationsrisiko wurde evaluiert. Ergebnisse: Ein abnormales femorales Gleitlager (Trochleadysplasie Typ C & D, path. Sulkuswinkel, path. LTI) hat einen direkten Einfluss auf die Entwicklung eines patello-femoralen Knorpelschadens im Langzeit-Follow-up (p für höhergradige TD = 0,009, path. Sulkuswinkel = 0,034, path. LTI = 0,003). Ähnliches gilt für die gesamte Studien-population (p für höhergradige TD = 0,006, path. LTI = 0,017). In der gesamten Studienpopulation nimmt die pathologische Knieversion ebenfalls Einfluss (p = 0,036). Es konnte kein Zusammenhang zwischen Luxationshäufigkeit und der pfA nachgewiesen werden (p > 0,05). Bei 20 betrachteten Risikofaktoren gibt es über 3 Milliarden Kombinationsmöglichkeiten. Führend tritt eine Kombination aus Patellahochstand, ver-größertem Sulkuswinkel und verkleinertem LTI auf (n = 18). Diskussion: Ein Zusammenhang zwischen APIFs mit (rezidivierenden) Patellaluxationen und (rezidivierenden) Patellaluxationen mit patellofemoralen Knorpelschäden wurde in Studien bestätigt. Naheliegend wäre eine direkte Beziehung zwischen APIFs und patello-femoralen Knorpelschäden. Sowohl in der gesamten Studienpopulation als auch an der Follow-up-Gruppe kann nur für ein pathologisches femorales Gleitlager (dysplastische Trochlea) eine signifikante Korrelation mit der Entwicklung einer pfA nachgewiesen werden. Risikofaktorkombinationen, die Patellaluxationen oder Knorpelschäden begünstigen, können nicht eindeutig identifiziert werden. Das Reluxationsrisiko wird durch einen lateralisierten Patellasehnenansatz (TTTG, TT-PCL, PT-PCL), Trochleadysplasie und vermehrter Femurtorsion erhöht. Es gibt zu viele Risikofaktorkombinationsmöglichkeiten, um den Einfluss auf Erstluxa-tionsalter und Reluxationsrisiko adäquat darzustellen. Zusammenfassung: Eine dysplastische Trochlea ist hauptverantwortlich für die pfA. Eine häufig auftretende Risikofaktorkombination der PFI findet sich nicht. Das Reluxa-tionsrisiko erhöht sich besonders durch eine dysplastische Trochlea und einen lateralisiertem Patellasehnenansatz., Introduction: The risk factors for patellofemoral instability (APIF) and lateral patellar dislocation (LPD) are well known. This study evaluates the impact of each APIF individually and in combination on the development of patellofemoral osteoarthritis (pfOA) and risk of patella redislocation. Material and Methods: A patellofemoral database was built. Patients with at least one LPD, complete medical record and MRI before surgical interventions for patellofemoral instability were selected. APIFs, such as patella position (ISI, CDI), trochlear dysplasia (Dejour-classification), TTTG, TT-PCL, PT-PCL, sulcus angle and lateral trochlear inclination were measured (n = 300). If available, leg alignment (MAD, HKA, mLDFA, MPTA) and rotation (femoral torsion according to Waidelich and modified Jarrett, tibial torsion, knee version) were analyzed. The correlation between APIFs and pfOA and the influence of age and number of dislocations were evaluated. The study group was filtered for long-term-follow-up-patients, who had an MRI at least 15 years after primary dislocation (n = 49). The relationship between APIFs and redislocation risk was checked. Results: An abnormal femoral trochlea shape (TD type C & D, path. sulcus angle, path. LTI) had direct impact on the development of pfOA in the follow-up-group (p for severe TD = 0,009, path. sulcus angle = 0,034, path. LTI = 0,003). pfOA was also significantly increased in the overall study population (p for severe TD = 0,006, path. LTI = 0,017). Pathological knee version has an effect on pfOA in the overall study population (p = 0,036). There was no correlation between dislocation rate and pfOA (p > 0,05). With 20 measured APIFs analyzed, more than 3 billion combinations are possible. Most common combination is patella alta with pathological sulcus angle and LTI (n = 18). Discussion: Studies confirmed the relationship between APIFs with (recurrent) LPD and (recurrent) LPD with pfOA. A direct relationship between APIFs on pfOA would seem logical. Concerning the overall study population and the follow-up-group only a patho-logical trochlea showed significant correlation towards pfOA development. APIF-combinations, which increase the risk for LPD could not be precisely identified. Lateralized patellatendon insertion (TTTG, TT-PCL, PT-PCL), trochlear dysplasia and increased femoral torsion increase the risk of recurrent LPD. There were too many APIF-combinations to check their effect on primary LPD-age and risk for recurrent LPD adequately. Conclusion: A dysplastic trochlea is primarily responsible for pfOA. A common riskfactor-combination for LDP could not be identified. Redislocation risk is increased by dysplastic trochlear and lateralized patella tendon insertion.

Published
2023

3. Traumatic Patellar Dislocation and Cartilage Injury: A Follow-up Study of Long-Term Cartilage Deterioration.

Author

Salonen, Essi E., Mäenpää, Heikki, Mattila, Ville M., Magga, Teemu, Kiekara, Tommi, and Sillanpää, Petri J.

Subjects
*ARTICULAR cartilage injuries, *ARTICULAR cartilage, *CHI-squared test, *FISHER exact test, *JOINT hypermobility, *KNEE diseases, *LONGITUDINAL method, *MAGNETIC resonance imaging, *OSTEOARTHRITIS, *PATELLA, *PROBABILITY theory, *T-test (Statistics), *DATA analysis software, *DESCRIPTIVE statistics, *MANN Whitney U Test, *DISEASE complications, *KNEE dislocation, *SYMPTOMS, *DIAGNOSIS, *THERAPEUTICS
Abstract

Background: Patellofemoral cartilage deterioration and osteoarthritis are reported to be associated with recurrent patellar dislocation. However, the association between first-time traumatic patellar dislocation and cartilage deterioration is unknown. Purpose: The aim of this study was to assess long-term cartilage deterioration in the patellofemoral and tibiofemoral joint after conservatively treated traumatic lateral patellar dislocation. Study Design: Case series; Level of evidence, 4. Methods: Twenty patients (mean age, 25 years) who sustained first-time traumatic lateral patellar dislocation with no previous patellofemoral instability symptoms were initially scanned with 1.5-T magnetic resonance imaging (MRI). A follow-up 3-T MRI was conducted, on average, 8 years after first-time lateral patellar dislocation. Subjective instability symptoms and Knee injury and Osteoarthritis Outcome Score were also assessed. Results: In the primary MRI, patellofemoral cartilage injury was seen in 14 of 20 patients (70%). Most (14/15) of the injuries were seen in the patellar cartilage, especially at the medial facet. On the follow-up MRI, patellofemoral cartilage deterioration was visible for all patients. The central patella (P = .005) seemed especially prone to cartilage deterioration during the follow-up. Half of the patients (10/20) had grade 3-4 cartilage lesions in the patellofemoral joint in the follow-up MRI. In the primary MRI, only 1 patient exhibited tibiofemoral joint cartilage lesions, whereas at the time of follow-up, 10 of 20 patients exhibited tibiofemoral cartilage lesions. The majority of these lesions were considered clinically nonsignificant (International Cartilage Repair Society = 1) and were seen in the lateral compartment (6/10, 60%). Of the 14 patients (36%) with injury to the patellar cartilage, 5 reported subsequent instability of the patellofemoral joint, but this was not associated with more significant cartilage deterioration in the follow-up MRI compared with patients without redislocation. Conclusion: While recurrent lateral patellar dislocation is known to lead to degenerative process, a single first-time or infrequently recurring traumatic lateral patellar dislocation also seems to be associated with gradual cartilage deterioration. Traumatic lateral patellar dislocation might initiate gradual degeneration of the cartilage in the patellofemoral joint and can lead to the development of generalized knee osteoarthritis. Instability symptoms of the patellofemoral joint, however, were not related to the severity of the deterioration. [ABSTRACT FROM AUTHOR]

Published
2017
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4. Traumatic Patellar Dislocation and Cartilage Injury: A Follow-up Study of Long-Term Cartilage Deterioration

Author

Tommi Kiekara, Essi E Salonen, Heikki Mäenpää, Petri J. Sillanpää, Teemu Magga, Ville M. Mattila, Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, and University of Tampere

Subjects
musculoskeletal diseases, Adult, Cartilage, Articular, Joint Instability, Male, medicine.medical_specialty, Recurrent patellar dislocation, Patellofemoral instability, Patellar Dislocation, Kirurgia, anestesiologia, tehohoito, radiologia - Surgery, anesthesiology, intensive care, radiology, Physical Therapy, Sports Therapy and Rehabilitation, Osteoarthritis, knee osteoarthritis, 03 medical and health sciences, Patellofemoral Joint, Young Adult, 0302 clinical medicine, Recurrence, Patellofemoral osteoarthritis, medicine, Cartilage injury, Humans, Orthopedics and Sports Medicine, lateral patellar dislocation, 030222 orthopedics, patellofemoral osteoarthritis, business.industry, Cartilage, patellofemoral instability, Follow up studies, cartilage deterioration, 030229 sport sciences, Middle Aged, Osteoarthritis, Knee, medicine.disease, Magnetic Resonance Imaging, Surgery, medicine.anatomical_structure, Patella, business, Follow-Up Studies
Abstract

Background:Patellofemoral cartilage deterioration and osteoarthritis are reported to be associated with recurrent patellar dislocation. However, the association between first-time traumatic patellar dislocation and cartilage deterioration is unknown.Purpose:The aim of this study was to assess long-term cartilage deterioration in the patellofemoral and tibiofemoral joint after conservatively treated traumatic lateral patellar dislocation.Study Design:Case series; Level of evidence, 4.Methods:Twenty patients (mean age, 25 years) who sustained first-time traumatic lateral patellar dislocation with no previous patellofemoral instability symptoms were initially scanned with 1.5-T magnetic resonance imaging (MRI). A follow-up 3-T MRI was conducted, on average, 8 years after first-time lateral patellar dislocation. Subjective instability symptoms and Knee injury and Osteoarthritis Outcome Score were also assessed.Results:In the primary MRI, patellofemoral cartilage injury was seen in 14 of 20 patients (70%). Most (14/15) of the injuries were seen in the patellar cartilage, especially at the medial facet. On the follow-up MRI, patellofemoral cartilage deterioration was visible for all patients. The central patella ( P = .005) seemed especially prone to cartilage deterioration during the follow-up. Half of the patients (10/20) had grade 3-4 cartilage lesions in the patellofemoral joint in the follow-up MRI. In the primary MRI, only 1 patient exhibited tibiofemoral joint cartilage lesions, whereas at the time of follow-up, 10 of 20 patients exhibited tibiofemoral cartilage lesions. The majority of these lesions were considered clinically nonsignificant (International Cartilage Repair Society = 1) and were seen in the lateral compartment (6/10, 60%). Of the 14 patients (36%) with injury to the patellar cartilage, 5 reported subsequent instability of the patellofemoral joint, but this was not associated with more significant cartilage deterioration in the follow-up MRI compared with patients without redislocation.Conclusion:While recurrent lateral patellar dislocation is known to lead to degenerative process, a single first-time or infrequently recurring traumatic lateral patellar dislocation also seems to be associated with gradual cartilage deterioration. Traumatic lateral patellar dislocation might initiate gradual degeneration of the cartilage in the patellofemoral joint and can lead to the development of generalized knee osteoarthritis. Instability symptoms of the patellofemoral joint, however, were not related to the severity of the deterioration.

Published
2017

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