Â鶹AV

What are musculoskeletal disorders?

Musculoskeletal disorders comprise a wide range of diseases that affect muscle, tendon, cartilage and bone, of which the arthritic diseases are the most well-known.

Together, the musculoskeletal diseases are the most common cause of chronic disability with a high cost for treatment due to their persistent nature. The combination of these factors places a significant personal and financial burden on individual patients, the NHS and society as a whole.

Many of these conditions are acquired later in life, thus the incidence and prevalence of musculoskeletal disorders are expected to continue to increase as the population ages. Musculoskeletal complaints are the most common chronic condition presented in primary care. According to , approximately 20 per cent of the adult population consults their general practitioner about a musculoskeletal condition each year. This range of conditions affects more lives and creates more disability than any other disease, but our understanding of how we develop them and how they progress is far from complete.

Over a period of several decades, together with Â鶹AV and Sussex Medical School, and the Royal Sussex County Hospital, the Â鶹AV has been investigating a wide range of disorders from degenerative conditions such as osteoarthritis and tendinopathies to autoimmune diseases like rheumatoid arthritis and lupus. 

Early diagnosis and the ability to predict outcomes of therapies are important elements in treating many musculoskeletal disorders, which affect bones, muscles and tendons. Through considering possible ways to provide earlier diagnoses and improved treatment options, researchers aim to limit pain and loss of function whilst improving quality of life and meeting the needs of an ageing population.

Research into muscle and tendon disorders

Musculoskeletal pathologies include disorders of muscles and tendons, which are often slow to repair. They affect people of all ages and activity levels, and impact on their ability to maintain an active, healthy lifestyle.

Many therapies have relied on weak or inadequate evidence for their implementation. This is partly due to the poor relationships between structural and functional measures of muscles and tendons during injury and recovery, making the task of targeting therapy and measuring objective outcomes difficult. Standard methods are available to determine tissue integrity, but these are confined to painful, invasive biopsies.

To make inroads into this, researchers have aimed at improving the diagnosis, understanding and treatment of muscle injury and tendon diseases. Using novel minimal and non-invasive methods they sought to measure tissue integrity and mechanical properties at rest and also under controlled stress. This was made possible by the development of ultrasound, elastography and magnetic resonance imaging (MRI) equipment that could image and determine the stiffness and resistivity of tendons, muscles and other related structures without them being removed from the body.

Researchers measured the mechanical and functional properties of muscle and tendon in vivo (i.e. with patients). By doing this, they aimed to develop a better understanding of the consequences of exercise, training, overtraining, injury and therapies on the time course of muscle and tendon anatomy and mechanical properties. They also applied isokinetic dynamometry, isometric force production, passive stiffness and ultrasonography combined with elastography techniques, developing and validating magnetic resonance imaging biomarkers that are able to reflect both metabolic and microstructural properties of muscular tissue.

What causes osteoarthritis? How is osteoarthritis research helping?

Osteoarthritis is characterised by the irreversible loss of articular cartilage which causes disability and pain. It is one of the top 10 disabling diseases in developed countries and the most common medical complaint affecting joints.

Osteoarthritis was once thought to be more correctly described as osteoarthrosis, categorising the disease as an abnormality (-osis) of the joint rather than an inflammatory disorder (-isis). However, more recently the role of pro-inflammatory mechanisms underlying the disease pathology has assumed a greater importance.

However our understanding of the initiation and progression of the disease is developing only slowly. Consequently treatment is typically limited to pain relief and joint replacement surgery.

Research at the Â鶹AV has focused on investigating the contribution of innate immune receptors and signalling pathways in the cells of the synovium and cartilage (chondrocytes). Using cellular and molecular techniques this research aims to bring about a better understanding of how tissue destruction and inflammation is initiated and maintained.

For example chondrocyte morphology has been observed to change in osteoarthritis cartilage, indicating a shift in cell phenotype. Researchers identified an increased number of these cells and their expression of the powerful inflammatory cytokine interleukin 1b (IL-1b) with the progression of osteoarthritis. Indeed, cell changes were observed in apparently normal articular cartilage suggesting a role in the initiation of the disease process. 

MicroRNAs (miRNAs) are small non-coding RNAs which are important regulators of gene expression in cells. These have recently been shown to exhibit different profiles in osteoarthritis compared to normal articular cartilage. Researchers have investigated their role in the inflammatory response in samples from patients with osteoarthritis.

A section through bovine articular cartilage with the articular surface uppermost. Live cells are stained with a green fluorescent dye (CMFDA) and dead cell nuclei stained red (propidium iodide). The image was acquired using a confocal laser scanning microscope.

Rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease that causes pain, swelling and damage of the joints. It is the second most common form of arthritis in the UK, more frequently affecting women than men, at a ratio of 3:1. The disease is characterised by persistent high levels of inflammation generated by activated immune cells that infiltrate the joints and release cytokines. This causes damage to the soft tissue, cartilage and bone causing deformity and loss of function. In addition, more widespread inflammation can occur which affects other parts of the body leading to complications of cardiovascular disease, fatigue and depression.

Research into rheumatoid arthritis seeks to improve our understanding of the disease mechanisms and treatment strategies with the ultimate aim of translating cutting-edge research into clinical practice.

The mechanisms that drive the persistent inflammation in rheumatoid arthritis are not fully understood. The inflammatory cytokines TNF and IL-6 are known to be important in maintaining the inflammation and joint damage. However, the pathways driving the production of these cytokines are still under investigation.

Potential candidates that may activate these pathways in rheumatoid arthritis are the toll-like receptors, a family of innate immune receptors and researchers at the Â鶹AV  demonstrated a potential role for these receptors in experimental arthritis models of arthritis and in cultures of human rheumatoid arthritis joint tissue. The studies aimed at investigating the expression, function and regulation of these receptors in immune cells from rheumatoid arthritis patients compared to healthy volunteers.

Novel targets for the treatment of rheumatoid arthritis

Traditionally, rheumatoid arthritis is treated clinically with anti-inflammatory drugs. In the twenty-first century, the clinical management of the disease has been improved substantially by the introduction of antibodies that target inflammatory cytokines or their receptors.However, the use of these therapies is limited because they are expensive. Also, the global suppression of cytokine function increases the potential for bacterial and fungal infections. In addition, not all patients respond to these therapies and some patients become unresponsive to treatment over time.

Reseaerchers have discovered an off-target anti-inflammatory effect of anti-depressant drugs. In experimental arthritis models these drugs can inhibit the progress of the disease and can reduce inflammatory cytokine production from human rheumatoid arthritis joint tissue. These  drugs indicated the potential to produce new therapies for rheumatoid arthritis in the future.

To achieve this goal, the mechanism by which these drugs are anti-inflammatory will need to be identified. Work is currently ongoing to uncover the exact target that the drugs interact with to generate the anti-inflammatory effect. Identification of the target will facilitate the design of potential new therapies for rheumatoid arthritis.

Non-joint symptoms of rheumatoid arthritis

Fatigue is one of the most common and debilitating symptoms experienced by patients with rheumatoid arthritis. However, little is known about how it is caused or how best to treat it. Interestingly, some treatments designed to reduce rheumatoid arthritis joint inflammation also dramatically reduce fatigue. How these medications reduce fatigue or why they work in only a fraction of the patients however is poorly understood.

Researchers have been investigating how these anti-­inflammatory medications reduce fatigue using a combination of brain imaging, sleep recordings, questionnaires and measures of peripheral inflammation, for example using functional magnetic resonance imaging (fMRI) to show that feelings of fatigue appear to be due to activation of a specific immune­ brain communication pathway. Among the research hypotheses tested have been tests as to whether anti-inflammatory medications improved fatigue in rheumatoid arthritis by de­activating this pathway. 

Understanding the mechanisms of rheumatoid arthritis fatigue offers the potential to develop targeted therapies for this common, highly disabling and presently neglected symptom. It may also help determine why these therapies are more helpful for treating fatigue in some patients than others.

Hands affected by rheumatoid arthritis

Diagram demonstrating the changes that occur to the synovial tissue, cartilage and bone in rheumatoid arthritis. Ongoing inflammation generated by infiltrating immune cells causes permanent damage to the joint.

Systemic lupus erythematosus

Resarch into Systemic Lupus Erythematosus (SLE) examines chronic inflammation in musculoskeletal diseases. SLE is an autoimmune disease that can affect any organ or tissue in the body and the symptoms can range from being mild to life threatening. With treatment, many patients experience sustained periods of remission but these are interrupted by disease flares producing symptoms that can be severe. These symptoms can include pain, chronic fatigue, depression and an inflammatory arthritis. Providing an early diagnosis is problematic and once diagnosed there is a lack of suitable treatments.  

The molecular mechanism of lupus is complex and poorly understood. It is characterised by high levels of interferon, the production of autoantibodies and complement activation. Some of these autoantibodies form immune complexes with DNA and RNA released from damaged cells. These complexes can activate toll-like receptors, a family of innate immune receptors that induce inflammation. Research has been investigating the expression, function and regulation of these receptors in immune cells from SLE patients compared to healthy volunteers.

Chronic inflammatory diseases are associated with oxidative stress. This causes oxidation of several biological targets (DNA, lipids and proteins). Protein oxidation can lead to loss of function of some key enzymes or cause a gain-of-function where normal proteins become antigenic or pro-inflammatory. Researchers have been studying protein oxidation, including the identification of the specific proteins oxidised. This research applies the basic knowledge acquired to date to the specific problem of musculoskeletal inflammatory diseases including SLE, considering, for example, whether the enzymes that control protein oxidation (glutaredoxin and thioredoxin) can regulate the inflammatory response and whether chronic inflammation is associated with increased oxidation of proteins; including secreted proteins and membrane proteins.

Molecular basis of pain

Chronic pain is reported to affect as many as one in five adults. It is debilitating and can substantially reduce the quality of life for the patient. Chronic pain is a major cause of long term sick leave and therefore has a significant impact on the economy.

Patients with chronic pain conditions such as repetitive strain injury, complex regional pain syndrome, compressive neuropathies and fibromyalgia frequently describe symptoms that are typically considered neuropathic. Symptoms include radiating pain, muscle aches, pain hypersensitivity (allodynia and hyperalgesia) and paresthesia. Although the central nervous system plays a major role in symptom production, it has become evident that central neuropathic pain mechanisms are driven by changes within the peripheral nervous system. Research at the Â鶹AV suggests that nerve inflammation (neuritis) may be in part responsible.

Results from laboratory studies suggest that patient symptoms can be generated from inflamed peripheral nerves in the absence of frank nerve injury. Professor Andrew Dilley showed that localised peripheral nerve inflammation can cause intact axons that transmit pain to become spontaneous and respond to direct mechanical stimulation (i.e. develop axonal mechanical sensitivity). Such physiological responses are consistent with clinical reports of spontaneous and radiating pain. A major focus for the laboratory was the cellular and molecular mechanisms that underlie changes in axonal excitability, in particular the role of chemokines and cytokines as modulators of neuronal activity, also ion channel expression and axonal transport changes in models of chronic pain that may lead to “hot spots” of axonal hyper-excitability.

Typical electrophysiological recordings from unmyelinated C fibre ‘pain’ nerves. Traces show electrical ‘firing’ of nerves following mechanical stimulation of an inflamed sciatic nerve.

Low back pain - the most common musculoskeletal dysfunction

Low back pain is the most common musculoskeletal dysfunction worldwide. This is a very costly disorder; it is estimated that 80 per cent of people will suffer from low back pain at some point in their lives. In the United Kingdom 49.1 per cent of the adult population experience back pain for more than a day in any one year. It has been estimated that in the UK 4.7 million working days were lost over a one year period due to conditions affecting the lower back. It is calculated that low back pain causes a much greater economic burden on society than other conditions such as coronary heart disease, rheumatoid arthritis and respiratory tract infections.

Research from researchers across the Â鶹AV and partners at Â鶹AV and Sussex Medical School (BSMS) have focused on increasing understanding of the physiological and functional mechanisms underpinning low back pain, evidencing treatment and management approaches to low back pain and increasing understanding of the experience of low back pain from the patients and clinicians’ perspectives. In collaboration with the NHS Physiotherapy Consultants across the South East of England, they have developed a novel patient recorded outcome measure used principally for patients with musculoskeletal dysfunction, primarily related to low back pain. 

Recent research on Musculoskeletal disorders from the Â鶹AV