Clinical trial NCT04128566: MechSens - Dose-response Relationship of in Vivo Ambulatory Load and Mechanosensitive Cartilage Biomarkers
Official title: MechSens - Dose-response Relationship of in Vivo Ambulatory Load and Mechanosensitive Cartilage Biomarkers: the Role of Age and Tissue Health
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Articular Cartilage Degeneration
Keywords: articular cartilage
mechanosensitive blood markers of articular cartilage
walking stress test
ambulatory load
articular cartilage thinning
anterior cruciate ligament (ACL) injury
articular cartilage quality
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2019-10-16
Enrollment: 87
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in serum levels of Interleukin 6 (IL-6), ( mechanosensitive blood marker of articular cartilage) in pg/ml
timeFrame: 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)
measure: Change in serum levels of Cartilage oligomeric matrix Protein (COMP) (mechanosensitive blood marker of articular cartilage) in U/l
timeFrame: 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)
measure: Change in serum levels of Matrix metallopeptidase (MMP)-3 (mechanosensitive blood marker of articular cartilage) in ng/ml
timeFrame: 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)
measure: Change in serum levels of Matrix metallopeptidase (MMP)-9 (mechanosensitive blood marker of articular cartilage) in ng/ml
timeFrame: 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)
measure: Change in serum levels of Proteoglycan (PGR)-4 (mechanosensitive blood marker of articular cartilage) in mg/ml
timeFrame: 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)
measure: Change in serum levels of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4) (mechanosensitive blood marker of articular cartilage) in ng/mL
timeFrame: 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)
Secondary outcomes:
measure: Change in modified Knee Society Score (KSS) score
timeFrame: Before walking stress test (t0= Baseline), at 12-month follow-up, at 24-month follow-up
measure: Change in modified Knee Injury and Osteoarthritis Outcome Score (KOOS) score
timeFrame: Before walking stress test (t0= Baseline), at 12-month follow-up, at 24-month follow-up
measure: Change in Physical activity (PA) level
timeFrame: during the 7 days prior to Baseline and during the Walking stress test (t0= Baseline)
measure: Joint kinematics and kinetics
timeFrame: during the Walking stress test (t0= Baseline)
measure: Change in heart rate (beats per minute)
timeFrame: During the walking stress test until 10 minutes after the stress test
measure: Change in T2 relaxation time from baseline to follow-up
timeFrame: MRI at least 7 days prior to the Walking stress test (t0= Baseline) and MRI 24 months after baseline
measure: Change in cartilage thickness from baseline to follow-up
timeFrame: MRI at least 7 days prior to the Walking stress test (t0= Baseline) and MRI 24 months after baseline
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: Department of Orthopaedics and Traumatology, University Hospital Basel
Study officials:
affiliation: Department of Orthopaedics and Traumatology, University Hospital Basel
name: Annegret Muendermann, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herger S, Vach W, Nuesch C, Liphardt AM, Egloff C, Mundermann A. Dose-response relationship of in vivo ambulatory load and mechanosensitive cartilage biomarkers-The role of age, tissue health and inflammation: A study protocol. PLoS One. 2022 Aug 19;17(8):e0272694. doi: 10.1371/journal.pone.0272694. eCollection 2022.