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Biomechanical-Based Protocol for in vitro Study of Cartilage Response to Cyclic Loading: A Proof-of-Concept in Knee Osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is an evolving disease and a major cause of pain and impaired mobility. A deeper understanding of cartilage metabolism in response to loading is critical to achieve greater insight into OA mechanisms. While physiological joint loading helps maintain cartilage integrity, reduced or excessive loading have catabolic effects. The main scope of this study is to present an original methodology potentially capable to elucidate the effect of cyclic joint loading on cartilage metabolism, to identify mechanisms involved in preventing or slowing down OA progression, and to provide preliminary data on its application. In the proposed protocol, the combination of biomechanical data and medical imaging are integrated with molecular information about chondrocyte mechanotransduction and tissue homeostasis. The protocol appears to be flexible and suitable to analyze human OA knee cartilage explants, with different degrees of degeneration, undergoing ex vivo realistic cyclic joint loading estimated via gait analysis in patients simulating mild activities of daily living. The modulation of molecules involved in cartilage homeostasis, mechanotransduction, inflammation, pain and wound healing can be analyzed in chondrocytes and culture supernatants. A thorough analysis performed with the proposed methodology, combining in vivo functional biomechanical evaluations with ex vivo molecular assessments is expected to provide new insights on the beneficial effects of physiological loading and contribute to the design and optimization of non-pharmacological treatments limiting OA progression.

SUBMITTER: Caravaggi P

PROVIDER: S-EPMC8126668 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Osteoarthritis (OA) is a multifactorial musculoskeletal disorder affecting mostly weight-bearing joints. Chondrocyte response to load is modulated by inflammatory mediators and factors involved in extracellular cartilage matrix (ECM) maintenance, but regulatory mechanisms are not fully clarified yet. By using a recently proposed experimental model combining biomechanical data with cartilage molecular information, basally and following ex-vivo load application, we aimed at improving the understanding of human cartilage response to cyclic mechanical compressive stimuli by including cartilage original anatomical position and OA degree as independent factors. Methods: 19 mono-compartmental Knee OA patients undergoing total knee replacement were recruited. Cartilage explants from four different femoral condyles zones and with different degeneration levels were collected. The response of cartilage samples, pooled according to OA score and anatomical position was tested ex-vivo in a bioreactor. Mechanical stimulation was obtained via a 3-MPa 1-Hz sinusoidal compressive load for 45-min to replicate average knee loading during normal walking. Samples were analysed for chondrocyte gene expression and ECM factor release. Results: Non parametric univariate and multivariate (generalized linear mixed model) analysis was performed to evaluate the effect of compression and IL-1β stimulation in relationship to the anatomical position, local disease severity and clinical parameters with a level of significance set at 0.05. We observed an anti-inflammatory effect of compression inducing a significant downmodulation of IL-6 and IL-8 levels correlated to the anatomical regions, but not to OA score. Moreover, ADAMTS5, PIICP, COMP and CS were upregulated by compression, whereas COL-2CAV was downmodulated, all in relationship to the anatomical position and to the OA degree. Conclusion: While unconfined compression testing may not be fully representative of the in-vivo biomechanical situation, this study demonstrates the importance to consider the original cartilage anatomical position for a reliable biomolecular analysis of knee OA metabolism following mechanical stimulation.

Project description:BackgroundThe global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine.MethodsThis proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks.DiscussionDuloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect.Trial registrationClinicalTrials.gov NCT04224584 . Registered on January 6, 2020. EudraCT 2019-003437-42 . Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019.

Project description:Introduction: Knee osteoarthritis (KOA) is characterized by articular cartilage degeneration. It has been widely accepted that the mechanical joint environment plays a significant role in the onset and progression of this disease. In silico models have been used to study the interplay between mechanical loading and cartilage degeneration, hereby relying mainly on two key mechanoregulatory factors indicative of collagen degradation and proteoglycans depletion. These factors are the strain in collagen fibril direction (SFD) and maximum shear strain (MSS) respectively. Methods: In this study, a multi-scale in silico modeling approach was used based on a synergy between musculoskeletal and finite element modeling to evaluate the SFD and MSS. These strains were evaluated during gait based on subject-specific gait analysis data collected at baseline (before a 2-year follow-up) for a healthy and progressive early-stage KOA subject with similar demographics. Results: The results show that both SFD and MSS factors allowed distinguishing between a healthy subject and a KOA subject, showing progression at 2 years follow-up, at the instance of peak contact force as well as during the stance phase of the gait cycle. At the peak of the stance phase, the SFD were found to be more elevated in the KOA patient with the median being 0.82% higher in the lateral and 0.4% higher in the medial compartment of the tibial cartilage compared to the healthy subject. Similarly, for the MSS, the median strains were found to be 3.6% higher in the lateral and 0.7% higher in the medial tibial compartment of the KOA patient compared to the healthy subject. Based on these intersubject SFD and MSS differences, we were additionally able to identify that the tibial compartment of the KOA subject at risk of progression. Conclusion/discussion: We confirmed the mechanoregulatory factors as potential biomarkers to discriminate patients at risk of disease progression. Future studies should evaluate the sensitivity of the mechanoregulatory factors calculated based on this multi-scale modeling workflow in larger patient and control cohorts.

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Biomechanical-Based Protocol for in vitro Study of Cartilage Response to Cyclic Loading: A Proof-of-Concept in Knee Osteoarthritis.

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