Metabolic responses of meniscal explants to injury and inflammation ex vivo

Cook, Alex E.; Stoker, Aaron M.; Leary, Emily; Pfeiffer, Ferris M.; Cook, James L.

doi:10.1002/jor.24045

Cited by 11 publications

(8 citation statements)

References 52 publications

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“…The menisci not only have a mechanical function in load transmission across the tibio‐femoral joint but also play an active role in the biologic environment in the joint. For instance, the meniscus produces key mediators of inflammation and matrix‐degrading enzymes in response to strain and chemical (cytokine) stimulation 15 . There is also crosstalk between meniscus and synovium, which may play a critical role in OA pathophysiology 16 .…”

Section: Discussionmentioning

confidence: 99%

Histologic and molecular features in pathologic human menisci from knees with and without osteoarthritis

Monibi

Pannellini

Otero

et al. 2021

Journal Orthopaedic Research

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The objective of this study was to evaluate histologic and molecular features of meniscus degeneration in cohorts of patients with and without osteoarthritis (OA) of the knee. Menisci were obtained from patients undergoing total knee arthroplasty for OA (TKA) or arthroscopic partial meniscectomy (APM) for a torn knee meniscus. Degenerative meniscal tears were among the most common tear type in the APM group based on the pattern. Using an integrative workflow for molecular evaluation of formalin‐fixed and paraffin‐embedded tissues, human menisci underwent blinded histologic evaluation and NanoString gene expression analyses. Histology revealed increased proteoglycan content in TKA menisci compared to APM menisci, but otherwise no significant differences in the total pathology score or sub‐scores between patients based on age or cohort. NanoString analyses revealed differential expression of genes primarily associated with the PI3K‐AKT signaling pathway, cell cycle, and apoptosis. These data provide new insights into histological and molecular features of meniscus degeneration in patients with and without knee OA. Histologic assessment of menisci showed similar severity of overall degeneration between cohorts, but there were differences at the molecular level. The dysregulated pathways identified in this study could contribute to early‐onset meniscus degeneration, or to a predisposition to meniscus tears and subsequent knee OA. Further studies that validate genes and pathways uncovered in this study will allow us to evaluate novel approaches to assess and treat meniscal degeneration.

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Section: Discussionmentioning

confidence: 99%

Histologic and molecular features in pathologic human menisci from knees with and without osteoarthritis

Monibi

Pannellini

Otero

et al. 2021

Journal Orthopaedic Research

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“…The role of the meniscus injury on PTOA progression may be related to the persistent intra-articular inflammatory response seen after ACL reconstruction [ 2 , 15 ]. We have demonstrated that pro-inflammatory stimulation of meniscus cells increases matrix metalloproteinase and cytokine activity [ 10 , 15 , 39 ]; the combination of pro-inflammatory cytokines and compressive loading, comparable to sporting and high demand activities, results in further degradative enzyme activity and increased production of pro-inflammatory mediators [ 40 ]. In this way, the meniscus plays an active role in promoting the cycle of articular cartilage degradation and PTOA progression after ACL reconstruction.…”

Section: Methodsmentioning

confidence: 99%

MOntelukast as a potential CHondroprotective treatment following Anterior cruciate ligament reconstruction (MOCHA Trial): study protocol for a double-blind, randomized, placebo-controlled clinical trial

Jacobs

Conley

Kraus

et al. 2022

Trials

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Background After anterior cruciate ligament (ACL) reconstruction, patient-reported outcomes are improved 10 years post-surgery; however, cytokine concentrations remain elevated years after surgery with over 80% of those with combined ACL and meniscus injuries having posttraumatic osteoarthritis (PTOA) within 10–15 years. The purpose of this multicenter, randomized, placebo-controlled trial is to assess whether a 6-month course of oral montelukast after ACL reconstruction reduces systemic markers of inflammation and biochemical and imaging biomarkers of cartilage degradation. Methods We will enroll 30 individuals undergoing primary ACL reconstruction to participate in this IRB-approved multicenter clinical trial. This trial will target those at greatest risk of a more rapid PTOA onset (age range 25–50 with concomitant meniscus injury). Patients will be randomly assigned to a group instructed to take 10 mg of montelukast daily for 6 months following ACL reconstruction or placebo. Patients will be assessed prior to surgery and 1, 6, and 12 months following surgery. To determine if montelukast alters systemic inflammation following surgery, we will compare systemic concentrations of prostaglandin E2, monocyte chemoattractant protein-1, and pro-inflammatory cytokines between groups. We will also compare degradative changes on magnetic resonance imaging (MRI) collected 1 and 12 months following surgery between groups with reductions in early biomarkers of cartilage degradation assessed with urinary biomarkers of type II collagen breakdown and bony remodeling. Discussion There is a complex interplay between the pro-inflammatory intra-articular environment, underlying bone remodeling, and progressive cartilage degradation. PTOA affects multiple tissues and appears to be more similar to rheumatoid arthritis than osteoarthritis with respect to inflammation. There is currently no treatment to delay or prevent PTOA after ACL injury. Since there is a larger and more persistent inflammatory response after ACL reconstruction than the initial insult of injury, treatment may need to be initiated after surgery, sustained over a period of time, and target multiple mechanisms in order to successfully alter the disease process. This study will assess whether a 6-month postoperative course of oral montelukast affects multiple PTOA mechanisms. Because montelukast administration can be safely sustained for long durations and offers a low-cost treatment option, should it be proven effective in the current trial, these results can be immediately incorporated into clinical practice. Trial registration ClinicalTrials.govNCT04572256. Registered on October 1, 2020.

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“…In addition to its mechanical role in load transmission in the knee, the meniscus is a bioactive tissue, responsive to proinflammatory stimuli ex vivo and a producer of degradative enzymes, proinflammatory cytokines, and inflammatory mediators. 1 Meniscus pathology is also associated with disease progression and pain in the knee joint, likely due to crosstalk with the synovium and other tissues. [2][3][4] The joint is an organ, and joint function and health are dependent upon the optimal interaction of all joint tissues, including meniscus, hyaline cartilage, subchondral bone, and synovium.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeted transcriptomic analyses of RNA isolated from formalin‐fixed and paraffin‐embedded human menisci

Monibi

Pannellini

Croen

et al. 2021

Journal Orthopaedic Research

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Formalin‐fixed and paraffin‐embedded (FFPE) biospecimens are a valuable and widely‐available resource for diagnostic and research applications. With biobanks of tissue samples available in many institutions, FFPE tissues could prove to be a valuable resource for translational orthopaedic research. The purpose of this study was to characterize the molecular profiles and degree of histologic degeneration on archival fragments of FFPE human menisci obtained during arthroscopic partial meniscectomy. We used FFPE menisci for multiplexed gene expression analysis using the NanoString nCounter® platform, and for histological assessment using a quantitative scoring system. In total, 17 archival specimens were utilized for integrated histologic and molecular analyses. The median patient age was 22 years (range: 14–62). We found that the genes with the highest normalized counts were those typically expressed in meniscal fibrocartilage. Gene expression differences were identified in patient cohorts based on age (≤40 years), including genes associated with the extracellular matrix and tissue repair. The majority of samples showed mild to moderate histologic degeneration. Based on these data, we conclude that FFPE human menisci can be effectively utilized for molecular evaluation following a storage time as long as 11 years. Statement of Clinical Significance: The integration of histological and transcriptomic analyses described in this study will be useful for future studies investigating the basis for biological classification of meniscus specimens in patients. Further exploration into the genes and pathways uncovered by this study may suggest targets for biomarker discovery and identify patients at greater risk for osteoarthritis once the meniscus is torn.

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Metabolic responses of meniscal explants to injury and inflammation ex vivo

Cited by 11 publications

References 52 publications

Histologic and molecular features in pathologic human menisci from knees with and without osteoarthritis

Histologic and molecular features in pathologic human menisci from knees with and without osteoarthritis

MOntelukast as a potential CHondroprotective treatment following Anterior cruciate ligament reconstruction (MOCHA Trial): study protocol for a double-blind, randomized, placebo-controlled clinical trial

Targeted transcriptomic analyses of RNA isolated from formalin‐fixed and paraffin‐embedded human menisci

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