There is an urgent demand for long term solutions to improve osteoarthritis treatments in the ageing population. There are drugs that control the pain but none that stop the progression of the disease in a safe and efficient way. Increased intervention efforts, augmented by early diagnosis and integrated biophysical therapies are therefore needed. Unfortunately, progress has been hampered due to the wide variety of experimental models which examine the effect of mechanical stimuli and inflammatory mediators on signal transduction pathways. Our understanding of the early mechanopathophysiology is poor, particularly the way in which mechanical stimuli influences cell function and regulates matrix synthesis. This makes it difficult to identify reliable targets and design new therapies. In addition, the effect of mechanical loading on matrix turnover is dependent on the nature of the mechanical stimulus. Accumulating evidence suggests that moderate mechanical loading helps to maintain cartilage integrity with a low turnover of matrix constituents. In contrast, nonphysiological mechanical signals are associated with increased cartilage damage and degenerative changes. This review will discuss the pathways regulated by compressive loading regimes and inflammatory signals in animal and
It is well established that mechanical loading regulates the structure and function of musculoskeletal tissues and helps maintain the functional integrity of articular cartilage and joint homeostasis. The onset and progression of osteoarthritis (OA) involves all the tissues of the joint initiated by multiple risk factors. These include joint instability and/or misalignment, obesity, previous knee injury, muscle weakness, age, and genetics. It is clear that joint tissues are sensitive to the magnitude, duration, and nature of the mechanical stimulus. A range of approaches have, therefore, been developed to examine the effect of mechanical loading on cartilage homeostasis and OA disease progression. However, each approach has limitations which make it difficult to evaluate the physiological relevance of the experimental findings. This review article will examine the role of abnormal joint loading in cartilage destruction and compare the findings to the protective effects of physiological loading in animal and
Cartilage defects in the knees of young or active individuals remain a problem in orthopaedic practice. The clinical symptoms of OA are joint pain, limitation of range of motion, and joint stiffness. Sports activities involving high intensity and repetitive loads increase the risk of OA and are most often associated with other injuries such as knee ligament tears, meniscal injuries, patellae fractures, and osteochondral lesions [
Overloading (e.g., traumatic or high intensity) induces morphological, molecular, and mechanical changes in cells and matrix which leads to softening, fibrillation, ulceration, and loss of cartilage [
Experimental evidence indicating the range of nonphysiological loading modalities in articular cartilage.
Type of load | Regimen | Model system | Major effect | Reference |
---|---|---|---|---|
Strenuous exercise | Running 40 km/day for one year | Beagle dogs | Decreased proteoglycan content in load bearing regions | [ |
Strenuous exercise | Running uphill on a treadmill for 40 weeks and 20 km/day for 15 weeks | Beagle dogs | Reduced GAG content in the superficial zone and reduced cartilage thickness | [ |
Immobilisation | 3 weeks | Adult dogs | Reduction in proteoglycan synthesis | [ |
Rigid immobilisation | 11 weeks | Canine knee | Decrease in cartilage thickness | [ |
Post ankle fracture model of partial load bearing | 7 weeks | 20 subjects with ankle fractures | Cartilage atrophy and reduced thickness in patellae and medial tibia | [ |
Joints are unloaded and restricted in movement | 24 months | 26 subjects with traumatic spinal cord injury | Progressive thinning of cartilage in the patella, medial tibia and decrease stiffness | [ |
Immobilisation and remobilisation | Initial 11 week immobilisation and subsequent 50 week remobilisation period | Canine knee | Immobilisation caused softening of tissue Remobilisation partially restored biomechanical properties | [ |
Single impact load | 15–20 MPa, 24 hrs | Bovine cartilage explants | Cell death and collagen damage | [ |
Impact load with variable peak stress | 4.5 to 20 MPa, 24 hrs | Bovine cartilage explants | Apoptosis (4.5 MPa), collagen breakdown (7–12 MPa), sGAG (6–13 MPa), and nitrite release (20 MPa) | [ |
High strain rate 0.1 and 1/sec | 18 and 24 MPa | Bovine cartilage explants | Reduction in protein biosynthesis and compressive/shear stiffness | [ |
High velocity single impact load | 24 hrs | Human and bovine cartilage explants | Matrix inhibition was more pronounced in bovine than human tissue | [ |
Repetitive impact load | 5 MPa, 0.3 Hz, 2 hrs | Bovine cartilage explants | Necrosis, apoptosis, followed by collagen and proteoglycan degradation | [ |
Static compression | 50%, 24 hours | Bovine cartilage explants | Inhibits proteoglycan synthesis and collagen type II | [ |
Reduced joint loading (e.g., static and immobilisation) leads to atrophy and degeneration of cartilage (Table
Several investigators have used a range of approaches to examine the effect of moderate exercise in maintaining cartilage homeostasis (Table
Clinical findings supporting a role for exercise therapy in maintaining cartilage health.
Intervention | Duration | Subjects | Outcome | Reference |
---|---|---|---|---|
Aerobic walking and quadriceps strengthening exercise | 18 months | 35 subjects without knee OA | Both exercise regimen showed normal distribution of proteoglycans and reduced pain and disability from knee OA | [ |
Supervised exercise | 3 times weekly for 4 months | 45 subjects who underwent partial medial meniscus resection 3–5 years previously | Improved GAG content and reduced pain and joint symptoms | [ |
Cumulative physical exercise | Low (<6862) or high (>8654) exercise hours | 805 subjects | Reduced risk in knee OA | [ |
Recreational walking or jogging | Low versus high levels of activity | 1279 subjects, with or without knee OA; middle aged or elderly, BMI below or above median | Subjects with a high BMI had no increase in risk of OA. Overweight, middle aged, and elderly persons neither protects against nor increases risk of OA | [ |
Exercise | Various | 11 randomised control trials | Beneficial effect on pain and disability | [ |
In most animal studies, load bearing exercise minimises the development of OA. For example, daily exercise increased proteoglycan content and cartilage thickness in hamster and rodent models [
Several
A comparison of animal and
Type of load | Regimen | Model system | Major effect | Reference |
---|---|---|---|---|
Running exercise | 6 to 12 km/day | Hamster | Increased proteoglycan content | [ |
Running exercise | 15 km over 28 days | Rat OA induced by ACLT | Reduced apoptosis and chondral erosions | [ |
Running exercise | Varied age, 15 months exercise | Rabbit | Improved collagen organisation in young and reversed OA in older animals | [ |
Increased loading | Increased loading following 8 weeks of splinting | Rabbit | Increased maturation of tissue and increased collagen content | [ |
Conditioning exercise | Increased workload by 30% | Foals | Reduced cartilage degeneration index | [ |
Running exercise | 4 km/day, uphill, 15 weeks | Beagle dogs | Increased proteoglycan content and cartilage thickness | [ |
Cyclic pressure-induced strain | 0.3 Hz, 6 hours | Human and monolayer | Increased aggrecan gene expression | [ |
Hydrostatic pressure | 5 and 10 MPa at 1 Hz for durations of 4 h per day for 4 days | Human monolayer | Increased aggrecan and collagen type II gene expression | [ |
Dynamic compression | 3% at 0.01 to 1 Hz, 43 days | Bovine and agarose | Increased proteoglycan and collagen synthesis | [ |
Dynamic compression | 15%, 1 Hz, 48 hours | Bovine and agarose | Increased cell proliferation and proteoglycan synthesis and reduced nitrite release | [ |
Dynamic compression | 10% at 1 Hz, 3 × 1 hr on, 1 hr off, 5 days/week for 21 days | Bovine and agarose | Increased equilibrium aggregate modulus, sGAG and collagen synthesis | [ |
Dynamic compression | 1 MPa, repeated 2 and 4 sec, 1.5 hour | Bovine and explants | Increased proteoglycan synthesis | [ |
Cyclic compression | 1 MPa, 0.5 Hz, 3 days | Bovine and explants | Increased proteoglycan synthesis | [ |
Chondrocytes will respond to excessive mechanical signals by disrupting the composition and structure of the extracellular matrix which reduces the biomechanical integrity of cartilage. Previous
Recent studies utilised a dietary model of obesity to examine the combined effect of mechanical overload and inflammatory mediators in cartilage degeneration [
A number of
The pathways of interactions between non-physiological mechanical signals and inflammatory cytokines will, therefore, involve a number of signalling routes (Figure
Effect of nonphysiological mechanical stimuli on signal transduction pathways in chondrocytes. Overloading activates the
Evidence from
Model depicting the potential protective effects of physiological mechanical stimuli in chondrocytes stimulated with interleukin-1
The critical mechanosensitive components include the integrins and cytoskeletal proteins (Figure
Moreover, mechanical stimuli may induce ERK due to the release of basic fibroblast growth factor (FGF-2) or cause cell membrane hyperpolarisation leading to an influx of calcium or sodium ions through putative mechanosensitive ion channels [
The need for novel pharmacological agents which provide effective long-term pain relief and have disease modifying properties for OA treatments is, as yet, unmet. Direct delivery of drugs such as glucocorticoid and hyaluronic acid formulations into the affected joint, do not retard the disease process and may provide only short-term pain relief [
A further option is to develop agents which synergise with physiological mechanical loading or which block the signal transduction pathways activated by abnormal mechanical stimuli. Stimulation of mechanoreceptors releases several soluble mediators in chondrocytes including ROS, prostaglandins, cytokines, growth factors, and neuropeptides. These mediators activate downstream signalling events that regulate gene expression and cell function. For example, anti-inflammatory cytokines (IL-4 and IL-10), growth factors (TGF
In addition, matrix deformation will cause bending of the primary cilia which stimulates connexin 43 (Cx43) hemichannels leading to ATP release and purinergic receptor activation [
The importance of mechanical loading in maintaining healthy joints and normal tissue remodelling has long been recognised. Previous
The authors would like to acknowledge funding from the AO Research Fund of the AO Foundation (S-09-83-C) and the Arthritis Research UK (19646 and 17026).