MechSens - Dose-response Relationship of in Vivo Ambulatory Load and Mechanosensitive Cartilage Biomarkers

University Hospital, Basel, Switzerland87 enrolled

Overview

This study is to investigate the effects of age, tissue status and the presence of inflammation on the in vivo dose-response relationship of ambulatory load and mechanosensitive blood markers of articular cartilage.

Articular cartilage is an avascular and aneural tissue that facilitates joint motion with minimal friction. Osteoarthritis (OA) is a joint disease that affects the whole joint resulting in severe articular cartilage degeneration with a prevalence worldwide of more than 10%. Although the molecular mechanisms that trigger the pathological changes in OA are largely unknown, the ability of chondrocytes to respond to load is believed to play a critical role in maintaining healthy tissue and in the initiation of OA. Different modes of ambulation have resulted in increases of specific blood markers, and immobilization during bed-rest lead to reductions in the same blood markers. However, the dose-response relationship between ambulatory load and mechanosensitive blood markers, its biological variation in healthy persons and in patients with a high risk of developing OA (e.g. with increasing age or after joint injury), and its relevance for cartilage degeneration are unknown. Based on reported differences in the magnitude of load-induced changes in blood markers of articular cartilage depending on the type of physical activity,an experimental framework of a systematic and controlled modulation of weight bearing during a walking stress test was previously tested and will be employed in this study. The following specific aims will be addressed: Specific Aim 1: Investigate the in vivo dose-response relationship between ambulatory load and mechanosensitive blood markers of articular cartilage using controlled weight bearing during a walking stress test and age, tissue status and the presence of inflammation as experimental paradigms. Specific Aim 2: Investigate the prognostic ability of the individual in vivo dose-response relationship between ambulatory load and mechanosensitive blood markers of articular cartilage for articular cartilage degeneration. Healthy subjects and subjects with previous anterior cruciate ligament (ACL) injury aged 20 to 50 years will be clinically assessed, undergo magnetic resonance imaging (MRI) of both knees, and complete questionnaires on physical function and physical activity. Participants will wear an activity monitor for the 7 days before and during the experiment to record their physical activity level. Each participant will complete three walking stress tests (30 minutes walking) on separate days with repeated blood sampling to assess load-induced changes in levels of mechanosensitive blood markers (COMP, MMP-3, PRG-4, ADAMTS-4). In each test, one of three different ambulatory loads will be applied (80, 100 and 120% body weight (BW)). Inflammation will be assessed as IL-6 serum concentration. Tissue status of articular knee cartilage will be assessed as MRI T2 relaxation time and cartilage thickness at baseline and at 24-month follow-up.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Enrollment

Conditions

Articular Cartilage Degeneration

Interventions

walking stress testPROCEDURE

walk for 30 minutes on a treadmill with either one of the three loading conditions (reduced load = 80% Bodyweight (BW), normal load = 100% BW, increased load = 120% BW). The order of experimental condition will be applied in randomized order determined by block randomization, and the same self-selected walking speed will be used for all conditions.

Eligibility

Sex: ALLMin age: 20 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria for group 1 and 3: * Being physically active (\>2hours/week) * No previous known knee injury: Inclusion Criteria for group 2 and 4: * Being physically active (\>2hours/week) * ACL rupture between 2 to 10 years prior to the study Exclusion Criteria: * Inability to provide informed consent * Age \< 20 years (before maturation) or age \> 60 years * Advanced general sarcopenia (degenerative loss of muscle mass in aging) and high likelihood of osteoarthritic changes * Body mass index (BMI) \> 35 kg/m2: * Excessive skin movement that influences the gait analysis * Inability to walk for 30 minutes * Contraindications for a knee MRI * Active rheumatic disorder * Prior neuromuscular impairment (e.g. stroke) * Conditions other than knee injury that could cause abnormal patterns of locomotion * Prior hip, knee, and ankle prosthesis * Osteotomy of the lower extremities - Prior spine surgery * Other major medical problems * Pregnancy * Investigators and their immediate families are not permitted to be subjects * Persons who have previously completed or withdrawn from this study * Patients currently enrolled in another experimental (interventional) protocol

Locations (1)

Department of Orthopaedics and Traumatology, University Hospital Basel

Basel, Switzerland

Outcomes

Primary Outcomes

Change in serum levels of Interleukin 6 (IL-6), ( mechanosensitive blood marker of articular cartilage) in pg/ml

Change in serum level of Interleukin 6 (IL-6), (mechanosensitive blood marker of articular cartilage) in pg/ml

Time frame: Before walking stress test (t0= Baseline), immediately after walking stress test (t1), 30-minutes after walking stress test (t2) and after two additional 90-minute resting intervals after walking stress test (t3 and t4)

Change in serum levels of Cartilage oligomeric matrix Protein (COMP) (mechanosensitive blood marker of articular cartilage) in U/l

Change in serum levels of Matrix metallopeptidase (MMP)-3 (mechanosensitive blood marker of articular cartilage) in ng/ml

Change in serum levels of Matrix metallopeptidase (MMP)-9 (mechanosensitive blood marker of articular cartilage) in ng/ml

Change in serum levels of Proteoglycan (PGR)-4 (mechanosensitive blood marker of articular cartilage) in mg/ml

Data from ClinicalTrials.gov

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Secondary Outcomes

Change in modified Knee Society Score (KSS) score

KSS consists of a total of 34 questions divided into four subscales which are rated separately. It consists of a Knee Score, which only rates the knee joint itself (e.g. pain, range of motion, stability and radiographic alignment), and a Function Score (patient's walking distance, climbing stairs and use of walking aids). The higher the score, the better the outcome in all subscales.

Time frame: Before walking stress test (t0= Baseline), at 12-month follow-up, at 24-month follow-up

Change in modified Knee Injury and Osteoarthritis Outcome Score (KOOS) score

The KOOS evaluates both short-term and long-term consequences of knee injury. It holds 42 items in 5 separately scored subscales; Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Recreation (Sport/Rec), and knee-related Quality of Life (QOL). The five KOOS subscales rate on a 5-point Likert-scale as extremely important, very important, moderately important, somewhat important, or not important at all.

Time frame: Before walking stress test (t0= Baseline), at 12-month follow-up, at 24-month follow-up

Change in Physical activity (PA) level

PA level ( number of steps taken, PA intensity) will be recorded using an activity monitor (ActiGraph GT3X+, Pensacola, FL, USA)

Time frame: during the 7 days prior to Baseline and during the Walking stress test (t0= Baseline)

Joint kinematics and kinetics

For the the three loading conditions at the Walking stress test, an inertial sensor system (RehaGait®, Hasomed GmbH, Magdeburg, Germany) will be used to collect joint angle curves at the ankle, knee and hip.

Time frame: during the Walking stress test (t0= Baseline)

Change in heart rate (beats per minute)

To assess and compare the cardiovascular stress subjects experience during the walking stress tests the heart rate will be measured.

Time frame: During the walking stress test until 10 minutes after the stress test

Change in T2 relaxation time from baseline to follow-up

Tissue status will be determined by the T2 relaxation time of weight bearing knee cartilage analyzed by Magnetic resonance Imaging (MRI) of both knees

Time frame: MRI at least 7 days prior to the Walking stress test (t0= Baseline) and MRI 24 months after baseline

Change in cartilage thickness from baseline to follow-up

Tissue status will be determined by the thickness of weight bearing knee cartilage analyzed by Magnetic resonance Imaging (MRI) of both knees

Time frame: MRI at least 7 days prior to the Walking stress test (t0= Baseline) and MRI 24 months after baseline